Aims

To investigate the effects of senescent osteocytes on bone homeostasis in the progress of age-related osteoporosis and explore the underlying mechanism.

Aims

cAMP response element binding protein (CREB1) is involved in the progression of osteoarthritis (OA). However, available findings about the role of CREB1 in OA are inconsistent. 666-15 is a potent and selective CREB1 inhibitor, but its role in OA is unclear. This study aimed to investigate the precise role of CREB1 in OA, and whether 666-15 exerts an anti-OA effect.

3D Printed polyether-ether-ketone (PEEK) has gained widespread use in clinical practice due to its excellent biocompatibility, biomechanical compatibility, and personalization. However, pre-printed PEEK implants are not without their flaws, including bioinert, optimization distortion of 3D printing digital model and prosthetic mismatching. Recent advancements in mechanical processing technology have made it possible to print bone implants with PEEK fused deposition, allowing for the construction of mechanically adaptable implants. In this study, we aimed to synthesize silanized polycitrate (PCS) via thermal polymerization and in situ graft it to PEEK surface to construct an elastomer coating for 3D printed PEEK implants (PEEK-PCS). This incorporation of PCS allows the implant to exhibit adaptive space filling ability and stress dispersal. In vivo and in vitro results, PEEK-PCS exhibited exceptional osseointegration and osteogenesis properties along with macrophage M2 phenotypic polarization, inflammatory factors reducing, promotion of osteogenic differentiation in bone marrow mesenchymal stem cells (BMSCs). Additionally, PEEK-PCS displays good autofluorescence properties in vitro and in vivo, with stable fluorescence for 14 days, suggesting potential bioimaging applications. The study confirms that PEEK in situ grafting with thermo-polymerized PCS elastomers is a viable approach for creating multifunctional (bone defect adaptation, bioimaging, immune regulation, and osseointegration) implants for bone tissue engineering.

Distal arthrogryposis (DA) is a collection of rare developmental disorders characterized by congenital joint contractures. Most arthrogryposis mutations are in muscle- and joint-related genes, and the anatomical defects originate cell-autonomously within the musculoskeletal tissues. However, gain-of-function (GOF) mutations in PIEZO2, a principal mechanosensor in somatosensation, cause DA subtype 5 via unknown mechanisms. We show that expression of a GOF PIEZO2 mutation in proprioceptive sensory neurons mainly innervating muscle spindles and tendons is sufficient to induce DA5-like phenotypes in mice. Overactive PIEZO2 causes anatomical defects via increased activity within the peripheral nervous system during postnatal development. Surprisingly, overactive PIEZO2 is likely to cause joint abnormalities via increased exocytosis from sensory neuron endings without involving motor circuitry. This reveals a role for somatosensory neurons: excessive mechanosensation within these neurons disrupts musculoskeletal development. We also present proof-of-concept that Botox injection or dietary treatment can counteract the effect of overactive PIEZO2 function to evade DA-like phenotypes in mice when applied during a developmental critical period. These approaches might have clinical applications. Beyond this, our findings call attention to the importance of considering sensory mechanotransduction when diagnosing and treating other musculoskeletal disorders.

Acknowledgements: Our work is supported by National Institutes of Health grant (R35 NS105067, R01 DE022358, R25 SC3GM127195, R25 GM07138, R01GM133845, intramural) and Howard Hughes Medical Institute.

Aims

To explore the novel molecular mechanisms of histone deacetylase 4 (HDAC4) in chondrocytes via RNA sequencing (RNA-seq) analysis.

Adequate visual clarity is paramount to performing arthroscopic shoulder surgery safely, efficiently, and effectively. The addition of epinephrine in irrigation fluid, and the intravenous or local administration of tranexamic acid (TXA) have independently been reported to decrease bleeding thereby improving the surgeon's visualization during arthroscopic shoulder procedures. No study has compared the effect of systemic administered TXA, epinephrine added in the irrigation fluid or the combination of both TXA and epinephrine on visual clarity during shoulder arthroscopy with a placebo group. The purpose of this study is to determine if intravenous TXA is a safe alternative to epinephrine delivered by a pressure-controlled pump in improving arthroscopic shoulder visualization during arthroscopic procedures and whether using both TXA and epinephrine together has an additive effect in improving visualization.

The design of the study was a double-blinded, randomized controlled trial with four 1:1:1:1 parallel groups conducted at one center. Patients aged ≥18 years undergoing arthroscopic shoulder procedures including rotator cuff repair, arthroscopic biceps tenotomy/tenodesis, distal clavicle excision, subacromial decompression and labral repair by five fellowship-trained upper extremity surgeons were randomized into one of four arms: Pressure pump-controlled regular saline irrigation fluid (control), epinephrine (1ml of 1:1000) mixed in irrigation fluid (EPI), 1g intravenous TXA (TXA), and epinephrine and TXA (EPI/TXA). Visualization was rated on a 4-point Likert scale every 15 minutes with 0 indicating ‘poor’ quality and 3 indicating ‘excellent’ quality. The primary outcome measure was the unweighted mean of these ratings. Secondary outcomes included mean arterial blood pressure (MAP), surgery duration, surgery complexity, and adverse events within the first postoperative week.

One hundred and twenty-eight participants with a mean age (± SD) of 56 (± 11) years were randomized. Mean visualization quality for the control, TXA, EPI, and EPI/TXA groups were 2.1 (±0.40), 2.1 (±0.52), 2.6 (±0.37), 2.6 (±0.35), respectively. In a regression model with visual quality as the dependent variable, the presence/absence of EPI was the most significant predictor of visualization quality (R=0.525; p < 0 .001). TXA presence/absence had no effect, and there was no interaction between TXA and EPI. The addition of MAP and surgery duration strengthened the model (R=0.529; p < 0 .001). Increased MAP and surgery duration were both associated with decreased visualization quality. When surgery duration was controlled, surgery complexity was not a significant predictor of visualization quality. No adverse events were recorded in any of the groups.

Intravenous administration of TXA is not an effective alternative to epinephrine in the irrigation fluid to improve visualization during routine arthroscopic shoulder surgeries although its application is safe. There is no additional improvement in visualization when TXA is used in combination with epinephrine beyond the effect of epinephrine alone.

Aims

Tissue inhibitors of metalloproteinases (TIMPs) are the endogenous inhibitors of the zinc-dependent matrix metalloproteinases (MMP) and A disintegrin and metalloproteinases (ADAM) involved in extracellular matrix modulation. The present study aims to develop the TIMPs as biologics for osteoclast-related disorders.

Correct femoral tunnel position in anterior cruciate ligament reconstruction (ACLR) is critical in obtaining good clinical outcomes. We aimed to delineate whether any difference exists between the anteromedial (AM) and trans-tibial (TT) portal femoral tunnel placement techniques on the primary outcome of ACLR graft rupture.

Adult patients (>18year old) who underwent primary ACLR between January 2011 – January 2018 were identified and divided based on portal technique (AM v TT). The primary outcome measure was graft rupture. Univariate analysis was used to delineate association between independent variables and outcome. Binary logistic regression was utilised to delineate odds ratios of significant variables.

473 patients were analysed. Median age at surgery was 27 years old (range 18–70). A total of 152/473, (32.1%) patients were AM group compared to 321/473 (67.9%) TT. Twenty-five patients (25/473, 5.3%) sustained graft rupture. Median time to graft rupture was 12 months (IQR 9). A higher odds for graft rupture was associated with the AM group, which trended towards significance (OR 2.03; 95% CI 0.90 – 4.56, p=0.081). Older age at time of surgery was associated with a lower odds of rupture (OR 0.92, 95% CI 0.86 – 0.98, p=0.014).

There is no statistically significant difference in ACLR graft rupture rates when comparing anteromedial and trans-tibial portal technique for femoral tunnel placement. There was a trend towards higher rupture rates in the anteromedial portal group.

Aims

LY3023414 is a novel oral phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitor designed for advanced cancers, for which a phase II clinical study was completed in March 2020; however, little is known about its effect on bone modelling/remodelling. In this study, we aimed to explore the function of LY3023414 in bone modelling/remodelling.

Aims

Parathyroid hormone (PTH) (1-34) exhibits potential in preventing degeneration in both cartilage and subchondral bone in osteoarthritis (OA) development. We assessed the effects of PTH (1-34) at different concentrations on bone and cartilage metabolism in a collagenase-induced mouse model of OA and examined whether PTH (1-34) affects the JAK2/STAT3 signalling pathway in this process.

Aims

The purpose of our study was to determine whether mesenchymal stem cells (MSCs) are an effective and safe therapeutic agent for the treatment of knee osteoarthritis (OA), owing to their cartilage regeneration potential.

Ulnar shortening osteotomy (USO) is a procedure performed to alleviate ulnar sided wrist pain caused by ulnar impaction syndrome (UIS) and/or triangular fibrocartilage complex (TFCC) injury. Presently, non-union rates for ulnar shortening osteotomy is quoted to be 0–18% in the literature. However, there is a dearth of literature on the effect of site of osteotomy and plate placement on the rate of complications like a delayed union, symptomatic hardware and need for second surgery for hardware removal. In this study, we performed a multi-centered institutional review of ulnar shortening osteotomies performed, focusing on plate placement (volar vs. dorsal) and osteotomy site (distal vs. proximal) and determining if it plays a role in reducing complications.

This study was a multi-centered retrospective chart review. All radiographs and charts for patients that have received USO for UIS or TFCC injury between 2013 and 2017 from hand and wrist fellowship-trained surgeons in Calgary, Alberta and Winnipeg, Manitoba were examined. Basic patient demographics including age, sex, past medical history, and smoking history were recorded. Postoperative complications such as delayed union, non-union, infection, chronic regional pain syndrome, hardware irritation requiring removal were evaluated with a two-year follow-up period. Osteotomy sites were analyzed based on the location in relation to the entire length of the ulna on forearm radiographs. Surgical techniques including volar vs. dorsal plating, oblique vs. transverse osteotomy cuts, and plate type were documented.

Continuous variables of interest were summarized as mean or medians with standard deviation or inter-quartile range as appropriate. Differences in baseline characteristics were determined by t-test or one-way ANOVA for continuous variables and chi-square or Fischer exact test for dichotomous variables. All analyses were conducted using SPSS V24.0 (Chicago, IL, USA). All statistical tests were considered significant if p < 0.05.

Between 2013–2017 there were 117 ulnar shortening osteotomies performed. The average age of patients was 46.2 ± 16.2, with 62.4% being female. The mean pre-operative ulnar variance was +3.89 ± 2.17 mm and post-operative ulnar variance was −1.90 ± 1.80 mm. 84.6% of the plates were placed on the volar aspect of the ulna and 14.5% were placed on the dorsal aspect. An oblique osteotomy was made 99.1% of the time. In measuring osteotomy placement, the average placement was made in the distal 1/3 of the ulna. Overall, there was a 40% complication rate. Hardware irritation requiring removal encompassed 23%, non-union 14%, and wound infection covered 0.8%. When comparing dorsal vs volar plating, there was no statistically significant difference for non-union or hardware removal. Similarly, in evaluating osteotomy level, there was no statistical difference between proximal vs distal osteotomy for non-union and hardware removal.

In this multi-centered retrospective review of ulnar shortening osteotomies, we found that there was an overall complication rate of 40%. There was no statistically significant difference in complication rates between dorsal vs volar plate placement or proximal vs distal osteotomy sites. Further studies examining other potential risk factors in lowering the complication rate would be beneficial.

Aims

Tibial plateau fractures (TPFs) are complex injuries around the knee caused by high- or low-energy trauma. In the present study, we aimed to define the distribution and frequency of TPF lines using a 3D mapping technique and analyze the rationalization of divisions employed by frequently used classifications.

During the pandemic of COVID-19, some patients with COVID-19 may need emergency surgeries. As spine surgeons, it is our responsibility to ensure appropriate treatment to the patients with COVID-19 and spinal diseases. A protocol for spinal surgery and related management on patients with COVID-19 has been reviewed. Patient preparation for emergency surgeries, indications, and contraindications of emergency surgeries, operating room preparation, infection control precautions and personal protective equipments (PPE), anesthesia management, intraoperative procedures, postoperative management, medical waste disposal, and surveillance of healthcare workers were reviewed. It should be safe for surgeons with PPE of protection level 2 to perform spinal surgeries on patients with COVID-19. Standardized and careful surgical procedures should be necessary to reduce the exposure to COVID-19.

Chondrocyte hypertrophy represents a crucial turning point during endochondral bone development. This process is tightly regulated by various factors, constituting a regulatory network that maintains normal bone development. Histone deacetylase 4 (HDAC4) is the most well-characterized member of the HDAC class IIa family and participates in different signalling networks during development in various tissues by promoting chromatin condensation and transcriptional repression. Studies have reported that HDAC4-null mice display premature ossification of developing bones due to ectopic and early-onset chondrocyte hypertrophy. Overexpression of HDAC4 in proliferating chondrocytes inhibits hypertrophy and ossification of developing bones, which suggests that HDAC4, as a negative regulator, is involved in the network regulating chondrocyte hypertrophy. Overall, HDAC4 plays a key role during bone development and disease. Thus, understanding the role of HDAC4 during chondrocyte hypertrophy and endochondral bone formation and its features regarding the structure, function, and regulation of this process will not only provide new insight into the mechanisms by which HDAC4 is involved in chondrocyte hypertrophy and endochondral bone development, but will also create a platform for developing a therapeutic strategy for related diseases.

Cite this article: Bone Joint Res. 2020;9(2):82–89.

Bone metastases are the most common cause of cancer-related pain and often lead to other complications such as pathological fractures and spinal cord compression. Bisphosphonates (BP) are a class of potent anti-resorptive agents commonly prescribed to retard osteoporosis progression. Interestingly, BP may have indirect anti-tumour properties through negative effects on macrophages, osteoclasts, endothelial cells and their ability to suppress matrix metalloproteinase (MMP) activity. Currently, the use of bisphosphonates for cancer therapy is generally restricted to high dose systemic delivery. The purpose of this study was to investigate the effects of direct local delivery of Zoledronate at the metastatic site in a mouse model of breast cancer metastasis to bone.

Seven days following intra-tibial inoculation with MDA-MB-231 (N = 1× 105) breast cancer cells in athymic mice, the experimental group (N = 11) was treated by direct infusion of 2µg of Zoledronate into the tibial lesion (three times/week for three weeks) and compared to vehicle-treated mice (N = 5). The formation of bone metastases and growth of the lesions were followed up by weekly bioluminescence imaging. In a subsequent experiment, a comparison of the effects of local versus systemic delivery of Zoledronate on the formation of osteolytic bone metastases was carried in athymic mice (N = 15). Seven days following intra-tibial inoculation with MDA-MB-231 breast cancer cells, the systemic group (N = 5) was treated with Zoledronate (0.025mg/kg) once per week for four weeks and compared to systemic delivery of vehicle (N = 4). Following treatment, the mice were sacrificed, and micro-CT images of the right tibia were obtained. Bone volume to tissue volume ratio (BV/TV%) was determined using µ-CT biomarkers.

The first experiment showed a statistically significant increase in mean bone volume/tissue volume ratio% (BV/TV%) in the treated group (7.0±1.54%) as compared to the control group (3.8±0.48%) (P <0.001, 95%CI=1.9–4.3). This corresponded to a net increase of 84.21% in response to Zoledronate treatment. Comparison between the local and systemic effects of Zoledronate also revealed a significant increase in the BV/TV% in the locally treated group (6.69±0.62%) when compared to the cohort administered systemic bisphosphonate treatment (4.03±0.44%) (P<0.001, 95%CI=1.24–3.20), corresponding to a net increase of 66.0%.

These preliminary results suggest that high dose sustained release of Zoledronate can lead to a significant inhibition of tumor-induced osteolysis. Moreover, comparison between local and systemic delivery revealed that the effect of local bisphosphonate administration exceeds the benefits of systemic delivery in terms of osteolysis inhibition. Lastly, the noted effects of Zoledronate local delivery triggers the need for further assessment of its anti-tumour activity.

Objective

To investigate the biomechanical mechanism and report preliminary clinical efficacy of eccentric rotational acetabular osteotomy (ERAO) when conduct treatment for developmental dysplasia of the hip (DDH).

Objective

To investigate the biomechanical basis and report preliminary clinical efficacy of eccentric rotational acetabular osteotomy (ERAO) when treating developmental dysplasia of the hip (DDH).

Implant-related infection (IRI) is closely related to the local immunity of peri-implant tissues. The generation of reactive oxygen species (ROS) in activated macrophages plays a prominent role in the innate immune response. In previous studies, we indicated that implant wear particles promote endotoxin tolerance by decreasing the release of proinflammatory cytokines. However, it is unclear whether ROS are involved in the damage of the local immunity of peri-implant tissues. In the present study, we assessed the mechanism of local immunosuppression using titanium (Ti) particles and/or lipopolysaccharide (LPS) to stimulate RAW 264.7 cells. The results indicate that the Ti particles induced the generation of a moderate amount of ROS through nicotinamide adenine dinucleotide phosphate oxidase-1 (NOX-1), but not through catalase. Pre-exposure to Ti particles inhibited ROS generation and extracellular regulated protein kinase (ERK) activation in LPS-stimulated macrophages. These findings indicate that chronic stimulation by Ti particles may lead to a state of oxidative stress and persistent inflammation, which may result in the attenuation of the immune response of macrophages to bacterial components such as LPS. Eventually, immunosuppression develops in peri-implant tissues, which may be a risk factor for IRI.

Osteotomy in spine and skull base surgery is a highly demanding task that requires very high precision. Compared to conventional surgical tools, laser allows contactless hard tissue removal with fewer traumas to the patient and higher machining accuracy. However, a key issue remains unsolved: how to terminate the ablation while the underlying critical soft tissue is reached?

Our research group has realised a closed-loop control of a CO₂-laser osteotomy system under the guidance of an optical coherence tomography (OCT). The OCT provides three-dimensional information about the microstructures beneath the bone surface with a resolution on micrometre scale and an imaging depth of about 0.5 mm. The OCT and CO₂-laser systems are integrated using a coaxial setup and a registration between their working spaces (mean absolute error 19.6 μm) was performed.

The laser ablation and OCT scan are performed in turn. After correction of image distortions and speckle noise reduction, the position of the critical structure can be segmented in the enhanced OCT scans. The laser parameters for the next round of ablation are foresightedly planned based on the overlying residual bone thickness. After patient motion compensation by tracking artificial landmarks in the OCT scans (accuracy: RMS 27.2 μm), the ablation pattern can be precisely carried out by the CO₂-laser. The system was evaluated by performing laser cochleostomy on native porcine cochlea and mean ablation accuracy of 30 μm has been achieved.

However, for narrow incisions that are only several tens of micrometres wide, very few pixels are visible beneath the incision bottom in the OCT and a robust segmentation of the critical structure is impossible. We are now developing a hybrid control system, which monitors the ablation-induced acoustic emission (AE) as a secondary control mechanism in addition to the OCT.

When a pre-defined “switching” depth is reached, the AE-based control module is activated. Instead of analysing the acquired signals with conventional Fourier transform, a wavelet transform-based approach has been developed, which compares the correlation coefficients of the wavelet spectra of successive laser pulses. At the transition from bone tissue to the underlying soft tissue layer, a significant change in the coefficients can be observed, which is regarded as the signal for terminating the ablation. In order to keep the injury to the soft tissue layer to a minimal level, the laser energy is reduced after the switching. Preliminary experiments revealed that the wavelet-based approach is capable of controlling the ablation using pulses with extremely low energy down to 0.04mJ/pulse, resulting in an injured tissue layer of less than 10 μm.

We expect to achieve the ablation accuracy on tens of micrometre scale using the proposed hybrid control mechanism.