Critical size bone defects are frequently caused by accidental trauma, oncologic surgery, and infection. Distraction osteogenesis (DO) is a useful technique to promote the repair of critical size bone defects. However, DO is usually a lengthy treatment, therefore accompanied with increased risks of complications such as infections and delayed union.

Herein, we developed an innovative intramedullary biodegradable magnesium (Mg) nail to accelerate bone regeneration in critical size bone defect repair during DO.

We observed that Mg nail induced almost 4-fold increase of new bone formation and over 5-fold of new vessel formation at 2 weeks after distraction. Mg nail upregulated the expression of calcitonin gene-related peptide (CGRP) in the new bone as compared with the DO alone group. We further revealed that blockade of the sensory nerve by overdose capsaicin blunted Mg nail enhanced critical size bone defect repair during the DO process. Moreover, inhibitors/antagonist of CGRP receptor, FAK, and VEGF receptor blocked the Mg nail stimulated vessel and bone formation.

In summary, we revealed, for the first time, a CGRP-FAK-VEGF signaling axis linking sensory nerve and endothelial cells, which may be the main mechanism underlying Mg-enhanced critical size bone defect repair when combined with DO, suggesting a great potential of Mg implants in reducing DO treatment time for clinical applications.

Aims

There is an increasing concern of osteoporotic fractures in the ageing population. Low-magnitude high-frequency vibration (LMHFV) was shown to significantly enhance osteoporotic fracture healing through alteration of osteocyte lacuno-canalicular network (LCN). Dentin matrix protein 1 (DMP1) in osteocytes is known to be responsible for maintaining the LCN and mineralization. This study aimed to investigate the role of osteocyte-specific DMP1 during osteoporotic fracture healing augmented by LMHFV.

Aims

This study aimed to explore whether serum combined with synovial interleukin-6 (IL-6) measurement can improve the accuracy of prosthetic joint infection (PJI) diagnosis, and to establish the cut-off values of IL-6 in serum and synovial fluid in detecting chronic PJI.

Previous study reported that intra-articular injection of MgSO4 could alleviate pain related behaviors in a collagenase induced OA model in rats. It provided us a good description on the potential of Mg2+ in OA treatment. However, the specific efficiency of Mg2+ on OA needs to be further explored and confirmed. The underlying mechanisms should be elucidated as well. Increasing attention has been paid on existence of synovial fluid MSCs (SF-MSCs) (not culture expanded) which may participate in endogenous reparative capabilities of the joint. On the other hand, previous studies demonstrated that Mg2+ not only promoted the expression of integrins but also enhanced the strength of fibronectin-integrin bonds that indicated the promotive effect of Mg2+ on cell adhesion, moreover, Mg2+ was proved could enhance chondrogenic differentiation of synovial membrane derived MSCs by modulating integrins. Based on these evidence, we hypothesize herein intra-articular injection of Mg2+ can attenuate cartilage degeneration in OA rat through modulating the biological behavior of SF-MSCs.

Human and rat SF-MSCs were collected after obtaining Experimental Ethics approval. The biological behaviors of both human and rat SF-MSCs including multiple differentiation, adhesion, colony forming, proliferation, etc. were determined in vitro in presence or absence of Mg2+ (10 mmol/L). Male SD rats (body weight: 450–500 g) were used to establish anterior cruciate ligament transection and partial medial meniscectomy (ACLT+PMM) OA models. The rats received ACLT+PMM were randomly divided into saline (control) group and MgCl2 (0.5 mol/L) group (n=6 per group). Intra-articular injection was performed on week 4 post-operation, twice per week for two weeks. Knee samples were harvested on week 2, 4, 8, 12 and 16 after injection for histological analysis for assessing the progression of OA. On week 2 and 4 after injection, the rat SF-MSCs were also isolated before the rats were sacrificed for assessing the abilities of chondrogenic differentiation, colony forming and adhesion in vitro. Statistical analysis was done using Graphpad Prism 6.01. Unpaired t test was used to compare the difference between groups. Significant difference was determined at P < 0 .05.

The adhesion and chondrogenic differentiation ability of both human and rat SF-MSCs were significantly enhanced by Mg2+ (10 mmol/L) supplementation in vitro. However, no significant effects of Mg2+ (10 mmol/L) on the osteogenic and adipogenic differentiation as well as the colony forming and proliferation. In the animal study, histological analysis by Saffranin O and Toluidine Blue indicated the cartilage degeneration was significantly alleviated by intra-articular injection of Mg2+, in addition, the expression of Col2 in cartilage was also increased in MgCl2 group with respect to control group indicated by immunohistochemistry. Moreover, the OARSI scoring was decreased in MgCl2 group as well. Histological analysis and RT-qPCR indicated that the chondrogenic differentiation of SF-MSCs isolated from Mg2+ treated rats were significantly enhanced compare to control group.

In the current study, we have provided direct evidence supporting that Mg2+ attenuated the progression of OA. Except for the effect of Mg2+ on preventing cartilage degeneration had been demonstrated in this study, for the first time, we demonstrated the promoting effect of Mg2+ on adhesion and chondrogenic differentiation of endogenous SF-MSCs within knee joint that may favorite cartilage repair. We have confirmed that the anti-osteoarthritic effect of Mg2+ involves the multiple actions which refer to prevent cartilage degeneration plus enhance the adhesion and chondrogenic differentiation of SF-MSCs in knee joint to attenuate the progression of OA. These multiple actions of Mg2+ may be more advantage than traditional products. Besides, this simple, widely available and inexpensive administration of Mg2+ has the potential on reducing the massive heath economic burden of OA. However, the current data just provided a very basic concept, the exact functions and underlying mechanisms of Mg2+ on attenuating OA progression still need to be further explored both in vitro and in vivo. Formula of Mg2+ containing solution also need to be optimized, for example, a sustained and controlled release delivery system need to be developed for improving the long-term efficacy.

Patellar fractures account for approximately 1% of all fractures. Open reduction and internal fixation is recommended to restore extensor continuity and articular congruity. However, complications such as nonunion and symptomatic hardware, still exist. Furthermore, there is a risk of re-fracturing of the healed bone during the removal of the implants. Magnesium (Mg), a biodegradable metal, has elastic moduli and compressive yield strength that are comparable to those of natural bone. Our previous study showed that released Mg ions enhanced fracture healing. However, Mg-based implants degrade rapidly after implantation and lead to insufficient mechanical strength to support the fracture. Microarc oxidation (MAO) is a metal surface coating that reduces corrosion. We hypothesized that Mg pins, with or without MAO, would enhance fracture healing radiologically, mechanically, and histologically, while MAO would decrease degradation of Mg pins.

Patellar fracture was performed on forty-eight 18-week-old female New Zealand White rabbits according to established protocol. Briefly, the patella is osteotomized transversely and a tunnel (1.1mm) was drilled longitudinally through the two bone fragments. A pin (1 mm, stainless steel, Mg, or MAO-Mg) was inserted into the tunnel. The reduced construct was stabilized with a figure-of-eight band wire (⊘ 0.6 mm stainless steel wire). Cast immobilization was applied for 6 weeks. The rabbits were euthanized at week 8 and 12 post-operation. Microarchitecture and mechanical properties of the repaired patella were analyzed with microCT and tensile testing respectively. Histological sections of the repaired patella were stained. To evaluate the effect of the MAO treatment on degradation rate of Mg pin, the volume of the Mg pins in the patella was measured with microCT.

At week 8, both Mg and Mg-MAO showed higher ratio of bone volume to tissue volume (BV/TV) than the control while there was no significant different between Mg and Mg-MAO. At week 12, Control, Mg, and Mg-MAO groups showed enlarged patella when compared to the normal patella. Tissue volume (TV) and bone volume (BV) of the patella in Mg and Mg-MAO were larger than those in the Control group. However, the Control had higher ratio of bone volume to tissue volume (BV/TV), TV density, and BV density than Mg and Mg-MAO. Tensile testing showed that the mechanical properties of the repaired patella (failure load, stiffness, ultimate strength, and energy-to-failure) of Mg and Mg-MAO were higher than that of the control at both week 8 and week 12. Histological analysis showed that there was significant new bone formation in the Mg and Mg-MAO group compared with the Control group at week 8 and 12. The degradation rate of the MAO-coated Mg pins was significantly slower than those without MAO at week 8 but no significant difference was detected at week 12.

Mechanical, microarchitectural, and histological assessments showed that Mg pins, with or without MAO, enhanced fracture healing of the repaired patella compared to the Control. MAO treatment enhanced the corrosion resistance of the Mg pins at the early time point.

Summary Statement

This study demonstrated that Sclerostin monoclonal antibody (Scl-Ab) enhanced bone healing in the rat osteotomy model. Scl-Ab increased callus size, callus bone volume fraction, rate of callus bone formation and fracture callus strength.

Introduction

Adolescent idiopathic scoliosis (AIS) is associated with low bone mineral density, which could be related to its etiopathogenesis. Apart from bone density, bone micro-architectures are equally important for better understanding of disease initiation and progression in AIS. Quantitative assessment of bone quality is hampered by the invasive nature of investigations, until recently when the high-resolution pQCT (XtremeCT) became available for revolutionary in-vivo microimaging and derivation of bone micro-architectural parameters. Our objective was to use this powerful instrument to study bone qualities in AIS and compare findings with those from healthy controls.

Introduction

The main challenge in management of adolescent idiopathic scoliosis (AIS) is to predict which curve will progress so that appropriate treatment can be given. We previously reported that low bone mineral density (BMD) was one of the adverse prognostic factors for AIS. With advancement in imaging technology, quantitative ultrasound (QUS) becomes a useful method to assess bone density and bone quality. The objective of this study was to assess the role of QUS as a radiation-free method to predict curve progression in AIS.

Bone tendon junction (BTJ) healing after injury is often slow, without restoration of fibrocartilage transition zone. Fibrocartilage formation has been observed near articular cartilage. It was hypothesised that articular cartilage interposition could stimulate fibrocartilage transition zone regeneration and improve BTJ healing.

Partial patellectomy repair was performed in goat. Articular cartilage harvested from excised patella segment was interposed between the patella and patellar tendon during repair. No cartilage interposition was used in control group. Samples were harvested at six, 12, and 24 weeks for histological examination (n=6 each). The histological images were digitised and analyzed using an image analysis system. Healing progress was assessed by the amount of new bone formation and fibrocartilage transition zone regeneration. Quantitative data were analyzed using SPSS version 14.0. Statistic al significance level was set at p < 0.05.

There was progressive increase in maximum new bone length and area of new bone formed with time (p< 0.05, Kruskal-Wallis test). No difference was observed between treatment groups. Articular cartilage interposition resulted in more fibrocartilage regeneration and higher proteoglycan uptake at all time points. At 24 weeks, length of fibrocartilage formed measured 7760 ± 629 μm with articular cartilage interposition, compared with 787± 274 μm in control (p = 0.002, Mann-Whitney test). Safranin O length measured 3301 ± 1236 μm with articular cartilage interposition, compared with 277 ± 187 μm in control (p = 0.03, Mann-Whitney test).

Autologous articular cartilage interposition stimulates fibrocartilage transition zone regeneration in BTJ repair without affecting bone formation.

Background: Adolescent Idiopathic Scoliosis is a 3-dimensional deformity of the spine affecting peri-pubertal adolescents (10-17-y) mostly. Although generalised osteopenia is well documented in AIS, the patho-physiology of AIS related osteopenia is uncertain.

Aim: We studied the association between pubertal-growth, BMD, bone-turnover, calcium intake (CA) and physical-activity (PA) in AIS and compared to those of healthy girls.

Methods: 894 girls (594 AIS & 300 healthy controls) aged 11–16-y entered the study. Anthropometric parameters, areal-BMD of the proximal-femur and volumetric-BMD of the distal-tibia were determined by Dual-x-ray-Absorptiometry and peripheral QCT respectively. Bone-turnover-markers: bone-alkaline-phosphatase (bALP) and deoxypyridonine (Dpd) were assayed. CA and weight-bearing PA were assessed by FFQ method.

Results: Weight of AIS at < 12-y and 13-y was significantly lower than controls (P< 0.05). From 13-y, corrected right and arm-span of AIS were significantly longer than the controls (P< 0.02). aBMD and vBMD were 6.7% and 8.4% respectively lower than the controls across the ages (P< 0.05). The disparity in BMD compared with controls increased with age. CA was not different between the AIS and controls (361 mg/d, IQR:230–532mg/d vs. 319 mg/d, IQR:220–494mg/d; P=0.063). Weight-bearing PA of AIS was significantly lower than those of controls (P< 0.02).

CA of AIS and controls reached < 40% of the Chinese calcium DRI (1000 mg/d). Both CA and weight-bearing PA were correlated with BMD in AIS (P< 0.04 & P=0.002 respectively). Both CA and PA were independent predictors on the variations of aBMDs (P< 0.03) and vBMDs (P< 0.04) in AIS after controlling for confounders in multivariate analysis. Regarding bone turn-over rate, bALP in AIS was 38.6% higher than the controls from 13-y onwards (P< 0.005) while Dpd of AIS was 30.4% lower than controls at age 15-y (P=0.003). Furthermore, bALP in AIS was negatively correlated with age-adjusted BMD (r=−0.34, P< 0.001) while the correlation was weaker in the controls (P=0.14, P< 0.002).

Conclusion: The correlation of calcium intake and physical activity with BMD occurred predominantly in AIS only and that these two factors were also independent determinants on BMD of AIS implying that calcium intake and physical activity were significant modulators on BMD in AIS. Significantly faster physical-growth, higher bone formation rate were associated with lower BMD. Osteopenia in AIS could be interplayed by abnormally faster pubertal-growth and bone-turnover. In fact, Calcium intake of AIS was too low to meet the calcium demand for bone-mineralization. A controlled calcium supplementation and programmed physical activity intervention trial is merited to confirm the effect of Calcium intake and physical activity on bone acquisition in AIS at peripubertal period.

Background: Low bone mass in patients with adolescent idiopathic-scoliosis has been well reported in cross-sectional studies. No large-scale longitudinal-study has been conducted to track bone-mineral-density (BMD) trajectory in peripubertal AIS with varying scoliosis-severity.

Aim: We evaluated the BMD trajectory and factors determining BMD accretion in AIS during peripubertal period.

Method: One hundred and ninety-six newly diagnosed AIS girls with Cobb-angle > 100 and 122 healthy girls, aged 12–15 years were followed-up for two years. Weight, height, leg length, menarche and Cobb-angle were determined. Areal lumbar-spinal BMD (LSBMD) and femoral-neck BMD (FNBMD), and volumetric distal-tibial BMD (TiBMD) were evaluated by dual-energy-x-ray-absorptiometry and peripheral QCT respectively. BMD growth-models were fitted by multilevel modelling (mixed longitudinal design).

Results: At baseline, 93% participants were pre-menarchial or within three years of menarche. Average Cobb-angles at baseline and subsequent follow-ups were 260, 230 and 260 respectively. TiBMD of AIS (moderate- and severe-severity) was significantly lower than the controls from 13–16 years (ANOVA, P< 0.05). Posthoc-test showed that TiBMD of severe-AIS was lower than moderate-AIS at 15–16 years (P< 0.05). LSBMD accrual was significantly lower among AIS (moderate- and severe-severity) than the controls from age 13–17 years (ANOVA, P< 0.05). FNBMD of AIS (moderate- and severe-severity) was lower than the controls at 15 years (ANOVA, P< 0.05). BMD trajectories of individuals differed inter-personally and intra-personally over time and that BMD growth followed a curvilinear pattern. The rates of BMD accretion reduced with retarded growth across peripubertal-period. Weight and height were significant time-varying predictors on BMD growth. BMD of AIS was persistently lower than the healthy girls throughout the study (P< 0.05).

Conclusions: This large-scale longitudinal study in AIS girls with moderate to severe-curve-severity showed for the first time that both the volumetric and areal BMD were persistently lower when compared to the age-matched healthy girls throughout 12–17 years. AIS with more severe curve-severity were found to have much lower BMD throughout the peripubertal period. Promotion of a higher bone-mass is important for AIS to modify scoliosis-progression and to achieve peak bone mass in order to reduce the risk of osteoporosis later in life.