Bone turnover and the accumulation of microdamage are impacted by the presence of skeletal metastases which can contribute to increased fracture risk. Treatments for metastatic disease may further impact bone quality. The present study aims to establish a preliminary understanding of microdamage accumulation and load to failure in osteolytic vertebrae following stereotactic body radiotherapy (SBRT), zoledronic acid (ZA), or docetaxel (DTX) treatment. Twenty-two six-week old athymic female rats (Hsd:RH-Foxn1rnu, Envigo, USA) were inoculated with HeLa cervical cancer cells through intracardiac injection (day 0). Institutional approval was obtained for this work and the ARRIVE guidelines were followed. Animals were randomly assigned to four groups: untreated (n=6), spine stereotactic body radiotherapy (SBRT) administered on day 14 (n=6), zoledronic acid (ZA) administered on day 7 (n=5), and docetaxel (DTX) administered on day 14 (n=5). Animals were euthanized on day 21. T13-L3 vertebral segments were collected immediately after sacrifice and stored in −20°C wrapped in saline soaked gauze until testing. µCT scans (µCT100, Scanco, Switzerland) of the T13-L3 segment confirmed tumour burden in all T13 and L2 vertebrae prior to testing. T13 was stained with BaSO. 4. to label microdamage. High resolution µCT scans were obtained (90kVp, 44uA, 4W, 4.9µm voxel size) to visualize stain location and volume. Segmentations of bone and BaSO. 4. were created using intensity thresholding at 3000HU (~736mgHA/cm. 3. ) and 10000HU (~2420mgHA/cm. 3. ), respectively. Non-specific BaSO. 4. was removed from the outer edge of the cortical shell by shrinking the segmentation by 105mm in 3D. Stain volume fraction was calculated as the ratio of BaSO. 4. volume to the sum of BaSO. 4. and bone volume. The L1-L3 motion segments were loaded under axial compression to failure using a µCT compatible loading device (Scanco) and force-displacement data was recorded. µCT scans were acquired unloaded, at 1500µm displacement and post-failure. Stereological analysis was performed on the L2 vertebrae in the unloaded µCT scans. Differences in mean stain volume fraction, mean load to failure, and mean bone volume/total volume (BV/TV) were compared between treatment groups using one-way ANOVAs. Pearson's correlation between stain volume fraction and load to failure by treatment was calculated using an adjusted load to failure divided by BV/TV. Stained damage fraction was significantly different between treatment groups (p=0.0029). Tukey post-hoc analysis showed untreated samples to have higher stain volume fraction (16.25±2.54%) than all treatment groups (p<0.05). The ZA group had the highest mean load to failure (195.60±84.49N), followed by untreated (142.33±53.08N), DTX (126.60±48.75N), and SBRT (95.50±44.96N), but differences did not reach significance (p=0.075). BV/TV was significantly higher in the ZA group (49.28±3.56%) compared to all others. The SBRT group had significantly lower BV/TV than the untreated group (p=0.018). Load divided by BV/TV was not significantly different between groups (p=0.24), but relative load to failure results were consistent (ZA>Untreated>DTX>SBRT). No correlations were found between stain volume fraction and load to failure. Focal and systemic cancer treatments effect microdamage accumulation and load to failure in osteolytic vertebrae. Current testing of healthy controls will help to further separate the effects of the tumour and cancer treatments on bone quality

Bone turnover and the accumulation of microdamage are impacted by the presence of skeletal metastases which can contribute to increased fracture risk. Treatments for metastatic disease may further impact bone quality. The present study aims to establish a preliminary understanding of microdamage accumulation and load to failure in osteolytic vertebrae following stereotactic body radiotherapy (SBRT), zoledronic acid (ZA), or docetaxel (DTX) treatment. Twenty-two six-week old athymic female rats (Hsd:RH-Foxn1rnu, Envigo, USA) were inoculated with HeLa cervical cancer cells through intracardiac injection (day 0). Institutional approval was obtained for this work and the ARRIVE guidelines were followed. Animals were randomly assigned to four groups: untreated (n=6), spine stereotactic body radiotherapy (SBRT) administered on day 14 (n=6), zoledronic acid (ZA) administered on day 7 (n=5), and docetaxel (DTX) administered on day 14 (n=5). Animals were euthanized on day 21. T13-L3 vertebral segments were collected immediately after sacrifice and stored in −20°C wrapped in saline soaked gauze until testing. µCT scans (µCT100, Scanco, Switzerland) of the T13-L3 segment confirmed tumour burden in all T13 and L2 vertebrae prior to testing. T13 was stained with BaSO. 4. to label microdamage. High resolution µCT scans were obtained (90kVp, 44uA, 4W, 4.9µm voxel size) to visualize stain location and volume. Segmentations of bone and BaSO. 4. were created using intensity thresholding at 3000HU (~736mgHA/cm. 3. ) and 10000HU (~2420mgHA/cm. 3. ), respectively. Non-specific BaSO. 4. was removed from the outer edge of the cortical shell by shrinking the segmentation by 105mm in 3D. Stain volume fraction was calculated as the ratio of BaSO. 4. volume to the sum of BaSO. 4. and bone volume. The L1-L3 motion segments were loaded under axial compression to failure using a µCT compatible loading device (Scanco) and force-displacement data was recorded. µCT scans were acquired unloaded, at 1500µm displacement and post-failure. Stereological analysis was performed on the L2 vertebrae in the unloaded µCT scans. Differences in mean stain volume fraction, mean load to failure, and mean bone volume/total volume (BV/TV) were compared between treatment groups using one-way ANOVAs. Pearson's correlation between stain volume fraction and load to failure by treatment was calculated using an adjusted load to failure divided by BV/TV. Stained damage fraction was significantly different between treatment groups (p=0.0029). Tukey post-hoc analysis showed untreated samples to have higher stain volume fraction (16.25±2.54%) than all treatment groups (p<0.05). The ZA group had the highest mean load to failure (195.60±84.49N), followed by untreated (142.33±53.08N), DTX (126.60±48.75N), and SBRT (95.50±44.96N), but differences did not reach significance (p=0.075). BV/TV was significantly higher in the ZA group (49.28±3.56%) compared to all others. The SBRT group had significantly lower BV/TV than the untreated group (p=0.018). Load divided by BV/TV was not significantly different between groups (p=0.24), but relative load to failure results were consistent (ZA>Untreated>DTX>SBRT). No correlations were found between stain volume fraction and load to failure. Focal and systemic cancer treatments effect microdamage accumulation and load to failure in osteolytic vertebrae. Current testing of healthy controls will help to further separate the effects of the tumour and cancer treatments on bone quality

Image-guided spine surgery requires registration between the patient anatomy and the preoperative computed tomography (CT) image. We have previously developed an accurate and robust registration technique for this application by using intraoperative ultrasound to acquire patient anatomy and then registering the ultrasound images to the CT images by aligning the posterior vertebral surfaces extracted from both modalities. In this study, we validate our registration technique across 18 vertebrae on three porcine cadavers. We applied the ultrasound-registration technique on the thoracic and lumbar vertebrae of the porcine cadavers using both single sweeps and double orthogonal sweeps. For each sweep pattern at each vertebra, we also randomly simulated 100 different initial misalignments and registered each misalignment. The resulting registration transformations are compared to gold standard registrations to assess the accuracy and the robustness of the technique. Orthogonal-sweep acquisition was found to be the sweep-pattern that performed the best and yielded a registration accuracy of 1.65 mm across all vertebrae on all porcine cadavers. It was found that the target registration errors (TRE) stay relatively constant with increasing initial misalignment and that the majority (82.7%) of the registrations resulted in TREs below the clinically recommended 2 mm threshold. In addition, it was found that the registration accuracy varies by the sweep pattern and the vertebral level, but neighbouring vertebrae tend to result in statistically similar accuracy. We found that our ultrasound-CT registration technique yields clinically acceptable accuracy and robustness on multiple vertebrae across multiple porcine cadavers

Quantitative assessment of metastatic involvement of the bony spine is important for assessing disease progression and treatment response. Quantification of metastatic involvement is challenging as tumours may appear as osteolytic (bone resorbing), osteoblastic (bone forming) or mixed. This investigation aimed to develop an automated method to accurately segment osteoblastic lesions in a animal model of metastatically involved vertebrae, imaged with micro computed tomography (μCT). Radiomics seeks to apply standardized features extracted from medical images for the purpose of decision-support as well as diagnosis and treatment planning. Here we investigate the application of radiomic-based features for the delineation of osteoblastic vertebral metastases. Osteoblastic lesions affect bone deposition and bone quality, resulting in a change in the texture of bony material physically seen through μCT imaging. We hypothesize that radiomics based features will be sensitive to changes in osteoblastic lesion bone texture and that these changes will be useful for automating segmentation. Osteoblastic metastases were generated via intracardiac injection of human ZR-75-1 breast cancer cells into a preclinical athymic rat model (n=3). Four months post inoculation, ex-vivo μCT images (µCT100, Scanco) were acquired of each rodent spine focused on the metastatically involved third lumbar vertebra (L3) at 7µm/voxel and resampled to 34µm/voxel. The trabecular bone within each vertebra was isolated using an atlas and level-set based segmentation approach previously developed by our group. Pyradiomics, an open source Radiomics library written in python, was used to calculate 3D image features at each voxel location within the vertebral bone. Thresholding of each radiomic feature map was used to isolate the osteoblastic lesions. The utility of radiomic feature-based segmentation of osteoblastic bone tissue was evaluated on randomly selected 2D sagittal and axial slices of the μCT volume. Feature segmentations were compared to ground truth osteoblastic lesion segmentations by calculating the Dice Similarity Coefficient (DSC). Manually defined ground truth osteoblastic tumor segmentations on the μCT slices were informed by histological confirmation of the lesions. The radiomic based features that best segmented osteoblastic tissue while optimizing computational time were derived from the Neighbouring Gray Tone Difference Matrix (NGTDM). Measures of coarseness yielded the best agreement with the manual segmentations (DSC=707%) followed by contrast, strength and complexity (DSC=6513%, 5428%, and 4826%, respectively). This pilot study using a radiomic based approach demonstrates the utility of the NGTDM features for segmentation of vertebral osteoblastic lesions. This investigation looked at the utility of isolated features to segment osteoblastic lesions and found modest performance in isolation. In future work we will explore combining these features using machine learning based classifiers (i.e. decision forests, support vector machines, etc.) to improve segmentation performance

Purpose. Maintenance of vertebral mechanical stability is of paramount importance to prevent pathologic fractures and resultant neurologic compromise in individuals with spinal metastases. Current non-surgical treatments for vertebral metastases (i.e. chemotherapy, bisphophonates (BP) and radiation) yield variable responses in the tumour and surrounding bone. Photodynamic therapy (PDT) is a novel, minimally-invasive technology that utilizes a drug activated by light at a specific non-thermal wavelength to locally destroy tumour cells. Previously, we observed that PDT can ablate cancer cells within bone and yield short-term (1-week) improvements in vertebral architecture and biomechanical strength, particularly when combined with BP therapy. This study aims to evaluate the effects of PDT in vertebral bone over a longer (6-week) time period, alone and combined with previous BP treatment, to determine if improvements in skeletal architecture and strength are maintained. Method. Fourty healthy rnu/rnu rats were randomly assigned to four treatment groups: (i) untreated control, (ii) BP only, (iii) PDT only and (iv) PDT following BP. BP treatments were administered on day 0 via subcutaneous injection of zoledronic acid. PDT was administered on day 7 via an intravenous injection of BPD-MA photosensitizer. A flat-cut optical fiber was inserted percutaneously adjacent to lumbar vertebra L2. After a 15-minute drug-light interval, 75J of light energy was delivered from a 690nm laser. Six weeks later, animals were euthanized. Structural properties of excised L2 vertebral bodies were quantified through semi-automated analysis of micro-CT images. In of the specimens, mechanical properties were evaluated by loading the L2 vertebral body to failure in axial compression. The remaining L2 vertebrae were analyzed for morphology, osteoid formation and osteoclast activity using histological methods. Results. Combined PDT+BP treatment yielded the largest increases in bone volume fraction (31%), trabecular thickness (45%) and vBMD (37%) and decreases in trabecular number (14%) and separation (26%) compared to untreated controls (n=10, all p<0.05). The cortical shell mass fraction was significantly lower than that of controls (24%) indicating increases in bone structure were primarily due to trabecular changes. Mechanically, PDT+BP treatment demonstrated a trend towards an increase in ultimate force compared to controls (n=5, p=0.176). BP-only and PDT-only treatments demonstrated similar trends to the combined treatment, but with a lower magnitude of effect. Qualitatively, histological analysis suggested more osteoid formation in groups receiving PDT, and a higher proportion of bone in BP-treated groups. Conclusion. PDT has a sustained positive effect on the mechanical and structural integrity of bone, particularly in combination with BP treatment. By ablating tumour tissue and strengthening bone, combined PDT+BP treatment presents as an attractive adjuvant minimally-invasive therapy for spinal metastasis

Reduced cervical spine canal AP diameter is linked to the development of spinal cord injury and myelopathy. This is of particular interest to clinicians in New Zealand, given a unique socio-ethnic make-up and prevalent participation in collision sport. Our study builds upon previous unpublished evidence, by analysing normal cervical spine CT scans to explore morphological differences in the sub-axial cervical spine canal, between New Zealand European, Māori and Paciāca individuals. 670 sub-axial cervical vertebrae (C3-C7) were analysed radiographically using high resolution CT trauma scans, showing no acute pathology with respect to the cervical spine. All measurements were made uPlising mulP-planar reconstruction software to obtain slices parallel to the superior endplate at each vertebral level. Maximal canal diameter was measured in the AP and transverse planes. Statistical analysis was performed using analysis of variance (ANOVA). We included 250 Maori, 250 NZ European and 170 Paciāca vertebrae (455 male, 215 female). Statistically and clinically signiācant differences were found in sagittal canal diameter between all ethnicities, at all spinal levels. NZ European vertebrae demonstrated the largest AP diameter and Paciāca the smallest, at all levels. Transverse canal diameter showed no signiācant difference between ethnicities, however the raatio of AP:transverse diameter was signiācantly different at all spinal levels except C3. Subjective morphological differences in the shape of the vertebral canal were noted, with Māori and Paciāca patients tending towards a flatter, curved canal shape. A previous study of 166 patients (Coldham, G. et al. 2006) found cervical canal AP diameter to be narrower in Māori and Paciāca patients than in NZ Europeans. Our study, evaluating the normal population, conārms these differences are likely reflecPve of genuine variation between these ethniciPes. Future research is required to critically evaluate the morphologic differences noted during this study

The purpose of this research was to determine the feasibility of radiostereometric analysis (RSA) as a diagnostic tool for assessing non-union following spinal arthrodesis procedures. Further, to estimate clinical thresholds for precision and accuracy of the proposed method in the cervical and lumbar spine. A three-level lumbo-sacral and a four-level cervical posterior arthrodesis procedures were performed on an artificial spine model (Sawbones, WA). Using a spring loaded inserter (RSA Biomedical, Sweden), eight to ten RSA markers were placed within each of the L4 and L5 segments in the spinous process (L4 only), lamina, transverse processes, posterior and anterior (down the pedicle) wall of the vertebral body. Eight to ten markers were placed within the proximal sacrum (S1) at the medial and lateral crests, tuberosity, and within the sacral canal wall. Four to eight RSA markers were placed into the C3-C6 lateral masses. Titanium screws and rods were applied to the spinal segments. Identical procedures were then performed on a cadaveric spine using similar bead placement and hardware. RSA imaging consisted of 12 double exams (24 exams) of the cervical and lumbar regions for both the Sawbones and cadaveric spine to assess precision of measurement under zero-displacement conditions. The most distal vertebrae were considered the datum against which the movement of all other vertebrae was compared. The artificial spine was then dismantled for accuracy assessment in which the middle vertebrae (L5 and C4-C5) were moved relative to the superior (L4 and C3) and inferior (S1 and C6) vertebrae by known, incremental displacements on an imaging phantom device. Displacements occurred along the superior-inferior, anterior-posterior, and flexion-extension (rotational) axes of motion. RSA images were obtained at each displacement. Image analysis was performed using model-based software (RSACore v3.41, Leiden, Netherlands) to visualize implanted RSA beads in 3-D space. Precision was defined as the 95% confidence interval of error in measuring zero-displacement. Accuracy was defined as the mean difference (with 95% confidence interval) between the known and measured displacement. The rate of RSA bead detection was high with 5–8 implanted beads being visible in both the lumbar and cervical regions of the artificial and cadaveric spines. Translational RSA precision for both spines was better than 0.25 mm and 0.82 mm for the lumbar and cervical regions, respectively. Rotational precision was better than 0.40° and 1.9° for the lumbar and cervical regions, respectively. RSA accuracy for the artificial spine overall demonstrated less than 0.11 mm translational bias (margin < ±0.02 mm) and less than 0.22° rotational bias (margin < ±0.15°). This study demonstrates that RSA achieves sufficient precision and accuracy to detect intervertebral micromotion for the purpose of assessing arthrodesis. Well dispersed RSA bead placement is critical to achieving sufficient accuracy as well as avoiding occlusion by metal hardware. Cervical bead implantation is particularly sensitive to bead clustering due to small vertebrae size and proximity to critical structures. The results of this work will aid in the development of a clinical study to assess arthrodesis in patients

Introduction. This research determines the feasibility of radiostereometric analysis (RSA) as a diagnostic tool for assessing fusion following spinal arthrodesis. Further, to estimate clinical thresholds for precision and accuracy of the proposed method in the cervical and lumbar spine. Methods. Two-level lumbo-sacral and three-level cervical posterior arthrodesis procedures were performed on an artificial spine model and a cadaveric spine (Figure 1). Using a spring-loaded inserter, RSA marker beads were placed within each of the L4-S1 and C3-C6 vertebrae, then analyzed for optimal bead distribution and detection. RSA imaging consisted of 12 double exams (24 exams) of the cervical and lumbar regions for both the Sawbones and cadaveric spine to assess precision of measurement under zero-displacement conditions, defined as the 95% confidence interval of error. Accuracy assessment was performed on the Sawbones model in which the middle vertebrae (L5 and C4-C5) were moved relative to the superior (L4 and C3) and inferior (S1 and C6) vertebrae by known, incremental displacements (Figure 2). RSA images were obtained at each displacement (Figure 3). Accuracy was defined as the mean difference between known and measured displacements. Results. Median RSA bead detection was 100% in cervical vertebrae and >75% in lumbar vertebrae in the artificial and cadaveric models. Translational RSA precision for both spine models was better than 0.25mm and 0.82mm for the lumbar and cervical regions, respectively. Rotational precision was better than 0.4° and 1.9° for the lumbar and cervical regions, respectively. RSA accuracy for the artificial spine overall demonstrated less than 0.11 mm translational bias (margin < ±0.02 mm) and less than 0.22° rotational bias (margin < ±0.15°). Discussion and Conclusion. This study demonstrates that RSA achieves sufficient precision and accuracy to detect intervertebral micromotion for the purpose of assessing arthrodesis. Well dispersed bead placement is critical to achieving sufficient accuracy and avoiding occlusion by metal hardware. The results of this work will aid in the development of a clinical study to assess arthrodesis in patients. For any figures or tables, please contact the authors directly

Introduction. From 2004 to 2015, elective lumbar fusions increased by 62% in the US. The largest increases were for among age 65 or older (139% in volume) and scoliosis (187%) [1]. Age is a well known factor of osteoporosis. The load-sharing may exceed the pedicular screws constructs in aging spine and lead to non-union and re-do. Surgical options may increase the screw purchase (e.g.: augmentation, extensions) at supplementary risks. Pedicular screw are known to cause vascular, nerve root or cord injuries. Facing these pitfalls, the surgeon's experience and rule of thumbs are the most deciding factors for the surgical planning. The aim of this study is to assess the accuracy of a patient specific tool, designed to plan a safe pedicular trajectory and to provide an intraoperative screw pullout strength estimate. Materials and Methods. Clinical QCT were taken for nine cadaveric spines (82 y. [61; 87], 6 females, 3 males). The experimental maximum axial pullout resistance (FMax) of twenty-seven pedicular screws inserted (nine T12, nine L4 and nine L5) was obtained as described in a previous study [2]. A custom 3D-WYSIWYG software simulated a medio-lateral surgical insertion technique in the QCTs coordinates reference, respecting the cortical walls. Repeatable density, morphometric and hardware parameters were recorded for each vertebrae. A statistical model was built to match predictive and experimental data. Preliminary results. Experimental FMax(N) were [104;953] (359 ±223). A further displacement of 1,81mm ±0,35 halved the experimental FMax. Predictive FMax(N) were [142;862] (359 ±220). A high positive correlation between experimental and predictive FMax was revealed (Pearson, ρ = 0.93, R2 = 0.87, p < .001, figure 1). Absolute differences ranged between 3N and 177N. Discussion. A high screw purchase in primary fixation is paramount to achieve spine surgical procedures (e.g.: kyphosis, scoliosis) and postoperative stability for vertebrae fusion. High losses of screw purchase by bone plastic deformation, begin with tiny pullouts. Theses unwanted intraoperative millimetric over-displacements are hard to avoid when monitoring at the same time tens of screws surrounded by bleedings. This advocates for including predictive FMax for each implantable pedicular screw in the surgical planning decision making process to prevent failures and assess risks. For the first time, this study presents an experimentally validated statistical model for FMax prediction with a safe trajectory definition tool, including patients’ vertebrae and hardware properties and referring to the patient's clinical 3D quantitative imagery. The model was able to differentiate between bone quality and vertebrae variations. More extensive model validation is currently ongoing to interface with robotics & navigation systems and to produce meshes for 3D printing of sterilizable insertion guides

Clinically significant proximal junctional kyphosis (PJK) occurs in 20% of children treated with posterior distraction-based growth friendly surgery. In an effort to identify modifiable risk factors, it has been theorized biomechanically that low radius of curvature (ROC) implants (i.e., more curved rods) may increase post-operative thoracic kyphosis, and thus may pose a higher risk of developing PJK. We sought to test the hypothesis that EOS patients treated with low ROC (more curved rods) distraction-based treatment will have a greater risk of developing PJK as compared to those treated with high ROC (straighter) implants. This is a retrospective review of prospectively collected data obtained from a multi-centre EOS database on children treated with rib-based distraction with minimum 2-year follow-up. Variables of interest included: implant ROC at index (220 mm or 500 mm), patient age, pre-operative scoliosis, pre-operative kyphosis, and scoliosis etiology. In the literature, PJK has been defined as clinically significant if revision surgery with superior extension of the upper instrumented vertebrae was performed. In 148 scoliosis patients, there was a higher risk of clinically significant PJK with low ROC (more curved) rods (OR: 2.6 (95%CI 1.09-5.99), χ2 (1, n=148) = 4.8, p = 0.03). Patients had a mean pre-operative age of 5.3 years (4.6y 220 mm vs 6.2y 500 mm, p = 0.002). A logistic regression model was created with age as a confounding variable, but it was determined to be not significant (p = 0.6). Scoliosis etiologies included 52 neuromuscular, 52 congenital, 27 idiopathic, 17 syndromic with no significant differences in PJK risk between etiologies (p = 0.07). Overall, patients had pre-op scoliosis of 69° (67° 220mm vs 72° 500mm, p = 0.2), and kyphosis of 48° (45° 220mm vs 51° 500mm, p = 0.1). The change in thoracic kyphosis pre-operatively to final follow up (mean 4.0 ± 0.2 years) was higher in patients treated with 220 mm implants compared to 500 mm implants (220 mm: 7.5 ± 2.6° vs 500 mm: −4.0 ± 3.0°, p = 0.004). Use of low ROC (more curved) posterior distraction implants is associated with a significantly greater increase in thoracic kyphosis which likely led to a higher risk of developing clinically-significant PJK in EOS patients

One out of nine Canadian males would suffer prostate cancer (PC) during his lifetime. Life expectancy of males with PC has increased with modern therapy and 90% live >10 years. However, 20% of PC-affected males would develop incurable metastatic diseases. Bone metastases (BM) are present in ~80% of metastatic PC patients, and are the most severe complication of PC, generating severe pain, fractures, spinal cord compression, and death. Interestingly, PC-BMs are mostly osteoblastic. However, the structure of this newly formed bone and how it relates to pain and fracture are unknown. Due to androgen antagonist treatment, different PC phenotypes develop with differential dependency on androgen receptor (AR) signaling: androgen-dependent (AR+), double negative (AR-) and neuroendocrine. How these phenotypes are related to changes in bone structure has not been studied. Here we show a state-of-the-art structural characterization of PCBM and how PC phenotypes are associated to abnormal bone formation in PCBM. Cadaveric samples (n=14) obtained from metastases of PC in thoracic or lumbar vertebrae (mean age 74yo) were used to analyze bone structure. We used micro-computed tomography (mCT) to analyze the three-dimensional structure of the bone samples. After imaging, the samples were sectioned and one 3mm thick section was embedded in epoxy-resin, ground and polished. Scanning electron microscopy (SEM)/energy-dispersive X-ray spectroscopy (EDS) and quantitative backscattering electron (qBSE) imaging were used to determine mineral morphology and composition. Another section was used for histological analysis of the PC-affected bone. Collagen structure, fibril orientation and extracellular matrix composition were characterized using histochemistry. Additionally, we obtained biopsies of 3 PCBM patients undergoing emergency decompression surgery following vertebral fracture and used them for immunohistological characterization. By using mCT, we observed three dysmorphic bone patterns: osteolytic pattern with thinned trabecula of otherwise well-organized structures, osteoblastic pattern defined as accumulation of disorganized matrix deposited on pre-existing trabecula, and osteoblastic pattern with minimum residual trabecula and bone space dominated by accumulation of disorganized mineralized matrix. Comparing mCT data with patho/clinical parameters revealed a trend for higher bone density in males with larger PSA increase. Through histological sections, we observed that PC-affected bone, lacks collagen alignment structure, have a higher number of lacunae and increased amount of proteoglycans as decorin. Immunohistochemistry of biopsies revealed that PC-cells inside bone organize into two manners: i) glandular-like structures where cells maintain their polarization in the expression of prostate markers, ii) diffuse infiltrate that spreads along bone surfaces, with loss of cell polarity. These cells take direct contact with osteoblasts in the surface of trabecula. We define that PCBM are mostly composed by AR+ with some double negative cells. We did not observe neuroendocrine phenotype cells. PCBMs generate predominantly osteoblastic lesions that are characterized by high lacunar density, lack of collagen organization and elevated proteoglycan content. These structural changes are associated with the infiltration of PC cells that are mostly androgen-dependent but have lost their polarization and contact directly with osteoblasts, perhaps altering their function. These changes could be associated with lower mechanical properties that led to fracture and weakness of the PCBM affected bone

Hip instability is one of the most common causes for total hip arthroplasty (THA) revision surgery. Studies have indicated that lumbar fusion (LF) surgery is a risk factor for hip dislocation. Instrumented spine fusion surgery decreases pelvic tilt, which might lead to an increase in hip motion to accommodate this postural change. To the best of our knowledge, spine-pelvis-hip kinematics during a dynamic activity in patients that previously had both a THA and LF have not been investigated. Furthermore, patients with a combined THA and LF tend to have greater disability. The purpose was to examine spine-pelvis-hip kinematics during a sit to stand task in patients that have had both THA and LF surgeries and compare it to a group of patients that had a THA with no history of spine surgery. The secondary purpose was to compare pain, physical function, and disability between these patients. This cross-sectional study recruited participants that had a combined THA and LF (n=10; 6 females, mean age 73 y) or had a THA only (n=11; 6 females, mean age 72 y). Spine, pelvis, and hip angles were measured using a TrakSTAR motion capture system sampled at 200 Hz. Sensors were mounted over the lateral thighs, base of the sacrum, and the spinous process of the third lumbar,12th thoracic, and ninth thoracic vertebrae. Participants completed 10 trials of a standardized sit-to-stand-to-sit task. Hip, pelvis, lower lumbar, upper lumbar, and lower thoracic sagittal joint angle range of motion (ROM) were calculated over the entire task. In addition, pain, physical function, and disability were measured with clinical outcomes: Hip Disability Osteoarthritis Outcome Score (pain and physical function), Oswestry Low Back Disability Questionnaire (disability), and Harris Hip Score (pain, physical function, motion). Physical function performance was measured using 6-Minute Walk Test, Stair Climb Test, and 30s Chair Test. Angle ROMs during the sit-to-stand-to-sit task and clinical outcomes were compared between THA+LF and THA groups using independent t-tests and effect sizes (d). The difference in hip ROM was approaching statistical significance (p=0.07). Specifically, the THA+LF group had less hip ROM during the sit-to-stand-to-sit task than the THA only group (mean difference=11.17, 95% confidence interval=-1.13 to 23.47), which represented a large effect size (d=0.83). There were no differences in ROM for pelvis (p=0.54, d=0.28) or spinal (p=0.14 to 0.97; d=0.02 to 0.65) angles between groups. The THA+LF group had worse clinical outcomes for all measures of pain, physical function, and disability (p=0.01 to 0.06), representing large effect sizes (d=0.89 to 2.70). Hip ROM was not greater in the THA+LF group, and thus this is unlikely a risk factor for hip dislocation during this specific sit-to-stand-to-sit task. Other functional tasks that demand greater excursions in the joints should be investigated. Furthermore, the lack of differences in spinal and pelvis ROM were likely due to the task and the THA+LF group had spinal fusions at different levels. Combined THA+LF results in worse clinical outcomes and additional rehabilitation is required for these patients

Proximal junctional kyphosis (PJK) is defined as adjacent segment kyphosis >10° between the upper instrumented vertebrae and the vertebrae 2 levels above following scoliosis surgery. There are few studies investigating the predictors and clinical sequelae involved with this relatively common complication. Our purpose was to determine the radiographic predictors of post-op PJK and to examine the association between PJK and pain/HRQOL following surgery for AIS. The Post-Operative Recovery after Scoliosis Correction: Home Experience (PORSCHE) study was a prospective multicenter cohort of AIS patients undergoing spinal fusion surgery. Pre-op and minimum 2 year f/u scoliosis and sagittal spinopelvic parameters (thoracic kyphosis–TK, lordosis–LL, pelvic tilt-PT, sacral slope-SS, pelvic incidence-PI) were measured and compared to numeric rating scale for pain (NRS) score, SRS-30 HRQOL and to the presence or absence of PJK (proximal junctional angle >100). Continuous and categorical variables were assessed using logistic regression and binomial variables were compared to binomial outcomes using chi-square. 163 (137 females) patients from 8 Canadian centers met inclusion criteria. At final f/u, PJK was present in 27 patients (17%). Pre-op means for PJK vs No PJK: Age 14.1 vs 14.7yr; females 85 vs 86%; scoliosis 57±22 vs 62±15deg; TK 28±18 vs 19±16deg ∗, LL 62±11 vs 60±12deg, PT 8±12 vs 10±10deg, SS 39±8 vs 41±9deg, PI 47±14 vs 52±13deg, SVA −9±30 vs −7±31mm. Final f/u for PJK vs No PJK: Scoliosis 20±11 vs 18±8deg, final TK 26±12 vs 19±10deg∗, LL 60±11 vs 57±12deg, PT 9±12 vs 12±13deg, SS 39±9 vs 41±9deg, PI 48±17 vs 52±14deg, SVA −23±26 vs −9±32mm∗. Significant findings: Pre-op kyphosis >40deg has an odds ratio (OR) of 4.41 (1.50–12.92) for developing PJK∗. The presence of PJK was not associated with any significant differences in NRS or SRS-30. ∗denotes p<0.05. This prospective multicenter cohort of AIS patients demonstrated a 17% risk of developing PJK. Pre-op thoracic kyphosis >40deg was associated with the development of PJK; however, the presence of PJK was not associated with increased pain or decreased HRQOL

Introduction. Pin-tract infections are a common problem in orthopaedic surgery, which limits the time an external fixator or Taylor spatial frame can be applied to a patient. The purpose of our study is to evaluate the ability of a novel implant surface coating — cationic steroid antibiotic (CSA)-44 — to delay or prevent the onset of these infections. This coating mimics endogenous antimicrobial peptides of the innate immune system and has been shown to effectively eradicate biofilms as well as prevent infection and stimulate healing of open, contaminated fractures. Methods. Surgeries were performed on 20 animals (outbred; Sprague-Dawley strain rats). Each animal received both CSA-coated and standard-of-care titanium pins, with pins randomized to the fifth or sixth vertebrae prior to surgeries. Animals were also randomized to either “Imaging” (imaging analysis) or “Infection” (microbiological analysis) cohorts. Surgeons were blinded to pin types and analyses cohorts. Digital images of pin sites were collected weekly over 12 weeks, and then graded by two orthopaedic surgery residents according to an established Likert scale. Graders were blinded to animal numbers, pin types, and timepoints (Figure 1). For the infection analysis cohort, four specimens per site were subjected to microbiological analysis from each site (i.e. pin, superficial skin swab, deep skin swab, sonicated bone). Each specimen was processed on three different microbiological plates (i.e. BAP, CAN, MAC) using standardized techniques. Imaging analysis was performed by dissecting vertebrae en bloc with pin retained, followed by fixation in 10% neutral buffered formalin for 72 hours. Following a graded ethanol series and storage in 70% ethanol, specimens were scanned with microcomputed tomography (µCT). Statistical analyses were performed to compare pin site appearance (chi-square testing) as well as total bacterial colony counts within each plate cohort and imaging data (Kruskal-Wallis testing); for all tests, significance was set at α=0.05. Results. Weekly digital images of each pin site were collected, graded, and then averaged (Figure 2). Statistical analysis showed no significant difference in pin appearance between the control and CSA pin cohorts at any timepoints. For the infection analysis cohort, bacterial colonies were counted on BAP, CAN, and MAC plates, followed by bacteria species identification (Figure3). Statistical analysis showed no significant difference in total bacterial colony counts between the control and CSA pin cohorts in any of the plate groups. For the imaging cohort, post-processing and subsequent data and statistical analyses are ongoing. Discussion. No significant differences were found between the control and CSA pin cohorts, with respect to pin appearance during the 12-week study or total bacterial colony counts on three plates, indicating that the control and CSA pins performed equivalently. Imaging analysis is ongoing. Although the environmentally-acquired infection model in an outbred rat strain was used to replicate the onset of pin tract infections in human populations, many animals showed Grade 1 or 2 pin site appearances at the 12-week endpoint. A follow-on study is underway using a direct bacterial seeding model. For any figures or tables, please contact the authors directly

The detailed biomechanical mechanism of annulus fibrosus under abnormal loading is still ambiguous, especially at the micro and nano scales. This study aims to characterize the alterations of modulus at the nano scale of individual collagen fibrils in annulus fibrosus after in-situ immobilization, and the corresponding micro-biomechanics of annulus fibrosus. An immobilization model was used on the rat tail with an external fixation device. Twenty one fully grown 12-week-old male Sprague-Dawley rats were used in this study. The rats were assigned to one of three groups randomly. One group was selected to be the baseline control group with intact intervertebral discs (n=7). In the other two groups, the vertebrae were immobilized with an external fixation device that fixed four caudal vertebrae (C7-C10) for 4 and 8 weeks, respectively. Four K-wires were fixed in parallel using two aluminum alloy cuboids which do not compress or stretch the target discs. The immobilized discs were harvested and then stained with hematoxylin/eosin, scanned using atomic force microscopy to obtain the modulus at both nano and micro scales, and analyzed the gene expression with real-time quantitative polymerase chain reaction. Significance of differences between the study groups was obtained using a two-way analysis of variance (ANOVA) with Fisher's Partial Least-Squares Difference (PLSD) to analyze the combined influence of immobilization time and scanning region. Statistical significance was set at P≤0.05. Compared to the control group, the inner layer of annulus fibrosus presented significant disorder and hyperplasia after immobilization for 8 weeks, but not in the 4 week group. The fibrils in inner layer showed an alteration in elastic modulus from 91.38±20.19MPa in the intact annulus fibrosus to 110.64±15.58MPa (P<0.001) at the nano scale after immobilization for 8 weeks, while the corresponding modulus at the micro scale also underwent a change from 0.33±0.04MPa to 0.47±0.04MPa (P<0.001). The upregulation of collagen II from 1±0.03 in control to 1.22±0.03 in 8w group (P = 0.003) was induced after immobilization, while other genes expression showed no significant alteration after immobilization for both 4 and 8 weeks compared to the control group (P>0.05). The biomechanical properties at both nano and micro scales altered in different degrees between inner and outer layers in annulus fibrosus after immobilization for different times. Meanwhile, the fibril arrangement disorder and the upregulation of collagen II in annulus fibrosus were observed using hematoxylin/eosin staining and real-time RT-PCR, respectively. These results indicate that immobilization not only influenced the individual collagen fibril at the nano scale, but also suggested alterations of micro-biomechanics and cell response. This work provides a better understanding of IVD degeneration after immobilization and benefits to the clinical treatment related to disc immobilization

As the intervertebral disc is largely avascular, needle injection is the most practical method for delivery of therapeutic agents used in treatments for degenerative disc disease. Intradiscal pressure increases during injection, and insufficient recovery time prior to needle retraction may result in injectate leakage. In order to determine the maximum pressure and post-injection recovery time for a given injection volume and rate, an analytical model of intradiscal injection was developed and calibrated experimentally. A governing equation was derived defining intradiscal pressure as a function of effective permeability, initial elastic stiffness, nonlinear stiffness term, and injection rate. The equation was solved using a fourth order Runge-Kutta routine with a 0.05s time step and a ramp-dwell injection. The model was calibrated by performing controlled intradiscal injections on five bovine caudal intervertebral discs. Three had adjacent vertebrae intact, while two were separated from vertebrae and constrained between porous stainless steel platens. A syringe driven by a linear actuator was used to inject phosphate buffered saline through a 21g hypodermic needle inserted radially into the disc to a depth of one half of the disc diameter. Injection was performed at a rate of 75μL/s to a volume of 250μL followed by a 240s dwell. Fluid pressure was recorded during both the injection phase and subsequent recovery phase. For each experimental pressure vs time trace, model parameters were varied in order to obtain an optimal fit. The model was run with the average parameter values across a grid of possible injection protocols, with injection volume ranging from 30 to 300μL and injection time ranging from 0.1 to 5s. For each case, peak pressure and time required to reach a 1kPa threshold were recorded. Experimentally measured peak pressure ranged from 68 to 88kPa. Pressure at the end of the 240s dwell ranged from 49 to 69kPa. There was no apparent difference between discs with and without endplates. Leakage of fluid following needle retraction was observed in all specimens. Experimental data were well fit by the analytical model, which predicted higher peak pressure and longer recovery time with increasing volume, from approximately 1500s at 30μL to nearly 3000s at 300μL. The model was nearly insensitive to injection rate. The experimental data confirm pressurization of the disc during injection and injectate leakage resulting from insufficient recovery time. The model predicts that the time required to recover to below threshold leakage pressure is impractically long for both laboratory and clinical injection protocols. Similar behavior with and without endplates confirms that fluid flow is limited by permeability of the tissue itself, not the boundary conditions. Slow recovery is likely attributable to the fact that peak injection pressures were lower than the hydraulic swelling pressure of the nucleus pulposus, which has been reported to be approximately 140kPa. Due to the high swelling pressure of the nucleus pulposus, it is unlikely that intradiscal injection procedures can be performed without substantial injectate leakage following needle retraction

Background. It is known that severe cases of intervertebral disc (IVD) disease may lead to the loss of natural intervertebral height, which can cause radiating pain throughout the lower back and legs. To this point, surgeons perform lumbar fusion using interbody cages, posterior instrumentation and bone graft to fuse adjacent vertebrae together, thus restoring the intervertebral height and alleviating the pain. However, this surgical procedure greatly decreases the range of motion (ROM) of the treated segment, mainly caused by high cage stiffness. Additive manufacturing can be an interesting tool to reduce the cage's elastic modulus (E), by adding porosity (P) in its design. A porous cage may lead to an improved osteointegration since there is more volume in which bone can grow. This work aims to develop a finite element model (FEM) of the L4-L5 functional spinal unit (FSU) and investigate the loss of ROM induced by solid and porous cages. Materials and Methods. The Intact-FEM of L4-L5 was created, which considered the vertebrae, IVD and ligaments with their respective material properties. 1. The model was validated by comparing its ROM with that of other studies. Moments of 10 Nm were applied on top of L4 while the bottom of L5 was fixed to simulate flexion, extension, lateral bending and axial rotation. 2. The lumbar cages, posterior instrumentation and bone graft were then modelled to create the Cage-FEMs. Titanium was chosen for the instrumentation and cages. Cages with different stiffness were considered to represent porous structures. The solid cage had the highest modulus (E. 0. =110 GPa, P. 0. =0%) whereas the porous cages were simulated by lowering the modulus (E. 1. =32.8 GPa, P. 1. =55%; E. 2. =13.9 GPa, P. 2. =76%; E. 3. =5.52 GPa, P. 3. =89%; E. 4. =0.604 GPa, P. 4. =98%), following the literature. 3. The IVD was removed in Cage-FEMs to allow the implant's insertion [Fig. 1] and the previous loading scenarios were simulated to assess the effects of cage porosity on ROM. Results. The Intact-FEM presents acceptable ROM according to experimental and numerical studies, as shown by the red line in Figure 2. After insertion, lower ROM values in Cage-FEMs are measured for each physiological movement [Fig. 3]. In addition, highly porous cages have greater ROM, especially in axial rotation. Discussion. Significant reduction of ROM is expected after cage insertion because the main goal of interbody fusion is to allow bone growth. As such, the procedure's success is highly dependent on segmental stability, which is achieved by using cages in combination with bone graft and posterior instrumentation. Furthermore, higher cage porosities seem to affect the FSU. In fact, ROM increases more as the cage modulus approaches that of the cancellous bone (E. canc-bone. =0.2 GPa. 1. ). Next step will be to assess the effects of cage design on the L4-L5 FSU mechanical behavior and stress distribution. To conclude, additive manufacturing offers promising possibilities regarding implant optimization, being able to create porous cages, thus reducing their stiffness. For any figures or tables, please contact the authors directly

Aim. Cutibacterium acnes is a significant cause of late-onset spinal implant infection (SII). In addition, usual preoperative prophylactic measures may be insufficient to prevent C. acnes operating site colonisation and infection, as demonstrated for prosthetic shoulder surgery. However, little information is available regarding risk factors for SII due to this microorganism. The aims of this study were to determine the characteristics of and risk factors for C. acnes SII. Method. we conducted a retrospective unmatched case-control study including all adult patients treated for mono and polymicrobial C. acnes SII during 2010–2015. Controls were randomly selected among patients diagnosed with SII due to other microorganisms during the same period. Results. Fifty-nine patients with C. acnes SII were compared with 59 controls. There was no difference in sex distribution (39% vs 53% men). Patients with C. acnes SII were younger (median age 42 vs. 65, p< 0.001), thinner (median body mass index (BMI) 21 vs. 25 kg/m. 2. , p< 0.001), and presented a better health status (ASA score≤ 2, 83% vs. 65%, p= 0.015; and presence of immunosuppression, 3% vs. 27%, p= 0.002). Patients with C. acnes SII were more likely to experience delayed/late infections (i.e. diagnosed >3 months post-instrumentation, 66% vs. 22%, p< 0.001) and to be instrumented for scoliosis (83% vs. 27%, p< 0.001) with an extended osteosynthesis (median number of fused vertebrae 12 vs. 5, p< 0.001). However, 20 C. acnes SII (34%) developed early (≤3 months) after instrumentation. The clinical presentation was significantly more indolent in the C. acnes group (presence of fever, 27% vs. 61%, p= 0.001; wound inflammation 39% vs. 61%, p< 0.001 and median C-reactive protein level 38 vs. 146 mg/L). Mixed C. acnes SII were diagnosed on 24 occasions (41%), 22 of which involving both C. acnes and staphylococcal strains. In the multivariate logistic regression model, factors independently associated with the development of SII involving C. acnes were age less than 65 (adjusted odds ratio [aOR] 7.13, 95% CI [2.44–24.4], p= 0.001), BMI< 22kg/m. 2. (aOR 3.71 [1.34–10.7], p= 0.012) and a number of fused vertebrae >10 (aOR 3.90 IC 95% [1.51–10.4], p= 0.005). Conclusions. There were significant differences between SII involving C. acnes and those involving other microorganisms. We identified a specific profile of patients at increased risk of developing C. acnes SII. These findings could contribute to improve both the prevention and treatment of such infections

Purpose. To develop a low complexity highly-automated multimodal approach to segment vertebral structure and quantify mixed osteolytic/osteoblastic metastases in the rat spine using a combination of CT and MR imaging. We hypothesize that semi-automated multimodal analysis applied to 3D CT and MRI reconstructions will yield accurate and repeatable quantification of whole vertebrae affected by mixed metastases. Method. Mixed spinal metastases were developed via intra-cardiac injection of canine Ace-1 luciferase transfected prostate cancer cells in a 3 week old rnu/rnu rat. Two sequential MR images of the L1-L3 vertebral motion segments were acquired using a 1H quadrature customized birdcage coil at 60 m isotropic voxel size followed by CT imaging at a 14m isotropic voxel size. The first MR image was T1 weighted to highlight the trabecular structure to ensure accurate registration with the CT image. The second MR image was T2 weighted to optimize differentiation between bone marrow and osteolytic tumour tissue. Samples were then processed for undecalcified histology and stained with Goldners Trichrome to identify mineralized bone and unmineralized new bone formation. All images were resampled to 34.9 m and manually aligned to a global axis. This was followed by an affine registration using a Quasi Newton optimizer and a Normalized Mutual Information metric to ensure accurate registration. The whole individual vertebrae and their trabecular centrums were then segmented from the CT images using an extended version of a previously developed atlas based registration algorithm. An intensity-based thresholding method was used to segment the regions corresponding to osteoblastic tumor predominantly attached to the outside of the cortical shell. The whole vertebral segmentation from the CT was warped around the T2 weighted MR to define the bone boundaries. An intensity-based thresholding approach was then applied to the T2 weighted MR segment the osteolytic tumor. Results. The customized MR coil acquired good quality images of both the bone and soft tissue structures in the spine. The CT based automated segmentation of the whole vertebrae and the trabecular centrums yielded high volumetric concurrency (∼90%) when compared to manually refined segmentations. Automated thresholding was even more robust in segmenting the individual trabecular networks and osteolytic tumours. The automation of the osteoblastic tumor segmentation was more challenging yielding concurrencies of ∼80% when compared to manually refined segmentations. Conclusion. We successfully combined CT and μMR imaging to accurately segment mixed metastatic lesions within rat vertebrae using a highly-automated algorithm. These segmentations could readily be used for quantitative evaluation of new and existing treatments aimed at skeletal metastases or to generate finite element models to evaluate biomechanical behaviour or fracture risk

Tungsten has been increasing in demand for use in manufacturing and recently, medical devices, as it imparts flexibility, strength, and conductance of metal alloys. Given the surge in tungsten use, our population may be subjected to elevated exposures. For instance, embolism coils made of tungsten have been shown to degrade in some patients. In a cohort of breast cancer patients who received tungsten-based shielding for intraoperative radiotherapy, urinary tungsten levels remained over tenfold higher 20 months post-surgery. In vivo models have demonstrated that tungsten exposure increases tumor metastasis and enhances the adipogenesis of bone marrow-derived mesenchymal stem cells while inhibiting osteogenesis. We recently determined that when mice are exposed to tungsten [15 ppm] in their drinking water, it bioaccumulates in the intervertebral disc tissue and vertebrae. This study was performed to determine the toxicity of tungsten on intervertebral disc. Bovine nucleus pulposus (bNP) and annulus fibrosus (bAF) cells were isolated from bovine caudal tails. Cells were expanded in flasks then prepared for 3D culturing in alginate beads at a density of 1×10. ∧. 6 cells/mL. Beads were cultured in medium supplemented with increasing tungsten concentrations in the form of sodium tungstate [0, 0.5, 5, 15 ug/mL] for 12 days. A modified GAG assay was performed on the beads to determine proteoglycan content and Western blotting for type II collagen (Col II) synthesis. Cell viability was determined by counting live and dead cells in the beads following incubation with the Live/Dead Viability Assay kit (Thermo Fisher Scientific). Cell numbers in beads at the end of the incubation period was determined using Quant-iT dsDNA Assay Kit (Thermo Fisher Scientific). Tungsten dose-dependently decreased the synthesis of proteoglycan in IVD cells, however, the effect was significant at the highest dose of 15 ug/mL. (n=3). Furthermore, although tungsten decreased the synthesis of Col II in IVD cells, it significantly increased the synthesis of Col I. Upregulation of catabolic enzymes ADAMTS4 and −5 were also observed in IVD cells treated with tungsten (n=3). Upon histological examination of spines from mice treated with tungsten [15 ug/mL] in their drinking water for 30 days, disc heights were diminished and Col I upregulation was observed (n=4). Cell viability was not markedly affected by tungsten in both bNP and bAF cells, but proliferation of bNP cells decreased at higher concentration. Surprisingly, histological examination of IVDs and gene expression analysis demonstrated upregulation of NGF expression in both NP and AF cells. In addition, endplate capillaries showed increases in CGRP and PGP9.5 expression as determined on histological sections of mouse IVDs, suggesting the development of sensory neuron invasion of the disc. We provide evidence that prolonged tungsten exposure can induce disc fibrosis and increase the expression of markers associated with pain. Tungsten toxicity may play a role in disc degeneration disease