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Majority of osteoporosis related fractures are treated surgically using metallic fixation devices. Anchorage of fixation devices is sometimes challenging due to poor osteoporotic bone quality that can lead to failure of the fracture fixation. Using a rat osteoporosis model, we employed neutron tomography and histology to study the biological effects of implant augmentation using an isothermally setting calcium sulphate/hydroxyapatite (CaS/HA) biomaterial with synthetic HA particles as recruiting moiety for systemically administered bisphosphonates. Using an osteoporotic sawbones model, we then provide a standardized method for the delivery of the CaS/HA biomaterial at the bone-implant interface for improved mechanical anchorage of a lag-screw commonly used for hip fracture fixation. As a proof-of-concept, the method was then verified in donated femoral heads and in patients with osteoporosis undergoing hip fracture fixation. We show that placing HA particles around a stainless-steel screw in-vivo, systemically administered bisphosphonates could be targeted towards the implant, yielding significantly higher peri-implant bone formation compared to un-augmented controls. In the sawbones model, CaS/HA based lag-screw augmentation led to significant increase (up to 4 times) in peak extraction force with CaS/HA performing at par with PMMA. Micro-CT imaging of the CaS/HA augmented lag-screws in cadaver femoral heads verified that the entire length of the lag-screw threads and the surrounding bone was covered with the CaS/HA material. X-ray images from fracture fixation surgery indicated that the CaS/HA material could be applied at the lag-screw-bone interface without exerting any additional pressure or risk of venous vascular leakage.
There is a lack of carriers for the local delivery of rifampicin (RIF), one of the cornerstone second defence antibiotic for Staphylococcus aureus deep bone infections (DBIs). RIF is also associated with systemic side effects, and known for causing rapid development of antibiotic resistance when given as monotherapy. We evaluated a clinically usedbi-phasic calcium sulphate/hydroxyapatite (CaS/HA) biomaterial as a carrier for dual delivery of RIF with vancomycin (VAN) or gentamicin (GEN). It was hypothesized that this combined approach could provide improved biofilm eradication and prevent the development of RIF resistance. Methods: 1) Biofilm eradication: Using a modified crystal violet staining biofilm quantification method, the antibiotics released at different time points (Day 1, 3, 7, 14, 21, 28 and 35) from the hemispherical pellets of CaS/HA(500 mg)-VAN (24.57 mg) / GEN (10.35 mg) composites with or without RIF (8.11 mg) were tested for their ability to disrupt the preformed 48-h old biofilms of S. aureus ATCC 25923, and S. aureus clinical strain P-3 in 96-well microtitre plate. For each tested group of antibiotic fractions, five separate wells were used (n=5). 2) Testing for resistance development: Similar to the method mentioned above the 48-h biofilm embeded bacteria exposed to antibiotic fractions from different time points continuously for 7 days. The biofilms remained were then tested for RIF resistant strains of bacteria. Overall, there was clear antibiofilm biofilm activity observed with CaS/HA-VAN/GEN+RIF combinations compared with CaS/HA-VAN/GEN alone. The S. aureus strains developed resistance to RIF when biofilms were subjected to CaS/HA-RIF alone but not with combinations of CaS/HA-VAN/GEN+RIF Enhanced antibiofilm effects without development of RIF resistance indicates that biphasic CaS/HA loaded with VAN or GEN could be used as a carrier for RIF for additional local delivery in clinically demanding DBIs.
Miniscrew implants (MSIs) are widely used to provide absolute anchorage for the orthodontic treatment. However, the application of MSIs is limited by the relatively high failure rate (22.86%). In this study, we wished to investigate the effects of amorphous and crystalline biomimetic calcium phosphate coating on the surfaces of MSIs with or without the incorporated BSA for the osteointegration process with an aim to facilitate the early loading of MSIs. Amorphous and crystalline coatings were prepared on titanium mini-pin implants. Characterizations of coatings were examined by Scanning electron microscopy (SEM), Confocal laser-scanning dual-channel-fluorescence microscopy (CLSM) and Fourier-transform infrared spectroscopy (FTIR). The loading and release kinetics of bovine serum albumin (BSA) were evaluated by Enzyme linked immunosorbent assay (ELISA). Activity of alkaline phosphate (ALP) was measured by using the primary osteoblasts. In vivo, a model of metaphyseal tibial implantation in rats was used (n=6 rats per group). We had 6 different groups: no coating no BSA, no coating but with surface adsorption of BSA and incorporation of BSA in the biomimetic coating in the amorphous and crystalline coatings. Time points were 3 days, 1, 2 and 4 weeks. Histological and histomorphometric analysis were performed and the bone to implant contact (BIC) of each group was compared. In vitro, the incorporation of BSA changed the crystalline coating from sharp plates into curly plates, and the crystalline coating showed slow-release profile. The incorporation of BSA in crystalline coating significantly decreased the activity of ALP in vitro. In vivo study, the earliest significant increase of BIC appeared in crystalline coating group at one week. The crystalline coating can serve as a carrier and slow release system for the bioactive agent and accelerate osteoconductivity at early stage in vivo. The presence of BSA is not favorable for the early establishment of osteointegration.
It has been established that mechanical stimulation benefits tendon-bone (T-B) healing, and macrophage phenotype can be regulated by mechanical cues; moreover, the interaction between macrophages and mesenchymal stem cells (MSCs) plays a fundamental role in tissue repair. This study aimed to investigate the role of macrophage-mediated MSC chondrogenesis in load-induced T-B healing in depth. C57BL/6 mice rotator cuff (RC) repair model was established to explore the effects of mechanical stimulation on macrophage polarization, transforming growth factor (TGF)-β1 generation, and MSC chondrogenesis within T-B enthesis by immunofluorescence and enzyme-linked immunosorbent assay (ELISA). Macrophage depletion was performed by clodronate liposomes, and T-B healing quality was evaluated by histology and biomechanics. In vitro, bone marrow-derived macrophages (BMDMs) were stretched with CELLOAD-300 load system and macrophage polarization was identified by flow cytometry and quantitative real-time polymerase chain reaction (qRT-PCR). MSC chondrogenic differentiation was measured by histochemical analysis and qRT-PCR. ELISA and qRT-PCR were performed to screen the candidate molecules that mediated the pro-chondrogenic function of mechanical stimulated BMDMs.Aims
Methods
Degenerative cervical spondylosis (DCS) is a common musculoskeletal disease that encompasses a wide range of progressive degenerative changes and affects all components of the cervical spine. DCS imposes very large social and economic burdens. However, its genetic basis remains elusive. Predicted whole-blood and skeletal muscle gene expression and genome-wide association study (GWAS) data from a DCS database were integrated, and functional summary-based imputation (FUSION) software was used on the integrated data. A transcriptome-wide association study (TWAS) was conducted using FUSION software to assess the association between predicted gene expression and DCS risk. The TWAS-identified genes were verified via comparison with differentially expressed genes (DEGs) in DCS RNA expression profiles in the Gene Expression Omnibus (GEO) (Accession Number: GSE153761). The Functional Mapping and Annotation (FUMA) tool for genome-wide association studies and Meta tools were used for gene functional enrichment and annotation analysis.Aims
Methods
There is a lack of biomaterial-based carriers for the local delivery of rifampicin (RIF), one of the cornerstone second defence antibiotics for bone infections. RIF is also known for causing rapid development of antibiotic resistance when given as monotherapy. This in vitro study evaluated a clinically used biphasic calcium sulphate/hydroxyapatite (CaS/HA) biomaterial as a carrier for dual delivery of RIF with vancomycin (VAN) or gentamicin (GEN). The CaS/HA composites containing RIF/GEN/VAN, either alone or in combination, were first prepared and their injectability, setting time, and antibiotic elution profiles were assessed. Using a continuous disk diffusion assay, the antibacterial behaviour of the material was tested on both planktonic and biofilm-embedded forms of standard and clinical strains of Aims
Methods
Although interlaminar endoscopic lumbar discectomy (IELD) is considered to be less invasive than microscopic lumbar discectomy (MLD) in treatment of lumbar herniated nucleus pulposus, the radiologic change of multifidus muscles by each surgery has rarely been reported. The aim of the present study was to compare the quantitative and qualitative changes of multifidus muscles between two surgical approaches and to analyze the correlation between various parameters of multifidus muscles and long term surgical outcome. 21 patients who received MLD and 18 patients who received IELD in a single tertiary hospital were enrolled and their preoperative, postoperative (≤15 days), and follow-up (≥6 months) MRIs were analyzed. The cross-sectional area (CSA) and fatty degeneration rate (FD) were quantitatively estimated at the level of surgery. The correlations among CSA, FD, body mass index, follow-up visual analogue scale(VAS) and Oswestry Disability Index(ODI) were assessed. Mean intervals of postoperative MRI and follow-up MRI from surgery were 3.0±3.7 days and 14.5±10.7 months, respectively. During the follow-up period, VAS was improved from 7.1±1.3 to 2.1±1.8 in MLD and from 8.2±1.4 to 2.2±1.8 in IELD. In cases of MLD, comparing with preoperative MRI, ipsilateral CSA was significantly increased in postoperative MRI (795.6mm2 vs. 906.5mm2, p<0.01), but it was not significantly different in follow-up MRI (795.6mm2 vs. 814.4mm2, p=1.00). However, in case of IELD, the ipsilateral CSAs in preoperative, postoperative, and follow-up periods were 892.0 mm2, 909.3 mm2, and 900.3 mm2, respectively. These changes were not significant over time (p=0.691). The ipsilateral FDs were not significantly changed between preoperative and follow-up periods in both MLD (21.4% vs. 20.9%, p=0.81) and IELD groups (23.5% vs. 21.8%, p=0.19). The increment of ipsilateral CSA had significant correlations with follow-up ODI (r=−0.368, p=0.02). Comparing with IELD, MLD induced more surgical trauma on multifidus muscle in postoperative period, but the muscular damage was recovered in follow-up period. IELD can minimize surgical trauma on multifidus muscle showing similar pain relief as MLD. Favorable surgical outcome in follow-up period may be related to increment of multifidus muscle volume. Figure 1 (A-C) The multifidus muscles in preoperative, postoperative, and follow-up periods, respectively, in patient with MLD. Comparing with preoperative period, the CSA of right multifidus muscle (ipsilateral side) was increased in postoperative period, but recovered in follow-up period. (D-F) The multifidus muscle in preoperative, postoperative, and follow-up periods, respectively, in patient with IELD. The CSA of left multifidus muscles (ipsilateral side) was not significantly changed over time. Comparing preoperative MRIs with follow-up MRIs, the FDs of multifidus muscles were not significantly changed regardless of surgical technique. Figure 2 The CSA was measured by marking region of interest (ROI) and FD was measured by calculating the rate of pixels beyond the threshold in ROI. All measurements were performed using ImageJ software (version 1.52a, National Institutes of Health, Bethesda, Maryland, USA). For any figures or tables, please contact the authors directly.
Transforming growth factor-beta2 (TGF-β2) is recognized as a versatile cytokine that plays a vital role in regulation of joint development, homeostasis, and diseases, but its role as a biological mechanism is understood far less than that of its counterpart, TGF-β1. Cartilage as a load-resisting structure in vertebrates however displays a fragile performance when any tissue disturbance occurs, due to its lack of blood vessels, nerves, and lymphatics. Recent reports have indicated that TGF-β2 is involved in the physiological processes of chondrocytes such as proliferation, differentiation, migration, and apoptosis, and the pathological progress of cartilage such as osteoarthritis (OA) and rheumatoid arthritis (RA). TGF-β2 also shows its potent capacity in the repair of cartilage defects by recruiting autologous mesenchymal stem cells and promoting secretion of other growth factor clusters. In addition, some pioneering studies have already considered it as a potential target in the treatment of OA and RA. This article aims to summarize the current progress of TGF-β2 in cartilage development and diseases, which might provide new cues for remodelling of cartilage defect and intervention of cartilage diseases.
The aims of this study were to develop an in vivo model of periprosthetic joint infection (PJI) in cemented hip hemiarthroplasty, and to monitor infection and biofilm formation in real-time. Sprague-Dawley rats underwent cemented hip hemiarthroplasty via the posterior approach with pre- and postoperative gait assessments. Infection with Aims
Methods
The aim of this meta-analysis was to assess the prognosis after early functional rehabilitation or traditional immobilization in patients who underwent operative or nonoperative treatment for rupture of the Achilles tendon. PubMed, Embase, Web of Science, and Cochrane Library were searched for randomized controlled trials (RCTs) from their inception to 3 June 2020, using keywords related to rupture of the Achilles tendon and rehabilitation. Data extraction was undertaken by independent reviewers and subgroup analyses were performed based on the form of treatment. Risk ratios (RRs) and weighted mean differences (WMDs) (with 95% confidence intervals (CIs)) were used as summary association measures.Aims
Methods
The morphology of medial malleolar fracture is highly variable and difficult to characterize without 3D reconstruction. There is also no universally accepeted classification system. Thus, we aimed to characterize fracture patterns of the medial malleolus and propose a classification scheme based on 3D CT reconstruction. We retrospectively reviewed 537 consecutive cases of ankle fractures involving the medial malleolus treated in our institution. 3D fracture maps were produced by superimposing all the fracture lines onto a standard template. We sliced fracture fragments and the standard template based on selected sagittal and coronal planes to create 2D fracture maps, where angles α and β were measured. Angles α and β were defined as the acute angles formed by the fracture line and the horizontal line on the selected planes.Aims
Methods
Targeted delivery of drugs is a major challenge in diseases such as infections and tumors. The aim of this study was to demonstrate that hydroxyapatite (HA) particles can act as a recruiting moiety for various bioactive molecules and as a proof-of-concept demonstrate that the affinity of drugs to hydroxyapatite can exert a biological effect. A bisphosphonate, zoledronic acid (ZA), was used as a model drug. Experiment 1 (ZA seeks HA): Calcium sulphate (CaS)/hydroxyapatite (HA) biomaterial pellets (diameter¸=5 mm, height=2 mm) were implanted in the abdominal muscle pouch of rats. After 2-weeks of implantation, a sub-cutaneous injection of 14C-ZA (0.1 mg/kg) was given. 24 h later, the animals were sacrificed and the uptake of ZA determined in the pellets using scintillation counting. Experiment 2 (Systemically administered ZA seeks HA and exerts a biological effect): A fenestrated implant was filled with the CaS/HA biomaterial and inserted in the proximal tibia of rats. 2-weeks post-op, a subcutaneous injection of ZA (0.1 mg/kg) was given. Animals were sacrificed at 6-weeks post-op. Empty implant was used as a control. Peri-implant bone formation was evaluated using different techniques such as micro-CT, mechanical testing and histology. Welch's t-test was used for mechanical testing and Mann-Whitney U test for micro-CT data analysis. Experiment 1: Uptake of radioactive ZA in the CaS/HA biomaterial was confirmed. Almost no ZA was present in the surrounding muscle. These results show high specific binding between systemically administered ZA and synthetic particulate HA. Experiment 2: Significantly higher peri-implant bone was measured using micro-CT in the group wherein the implant contained the CaS/HA biomaterial and ZA was administered systemically (This study presents a method for biomodulating HA in situ by different bioactive molecules. The approach of implanting a biomaterial capable of recruiting systemically given drugs and thereby activate the material is novel and may present a possibility to treat bone infections or tumors.
With promising antibiofilm properties, rifampicin is considered as a cornerstone in the complementary treatment of bone and joint infections. But, achieving an adequate concentration of rifampicin long-term in bone tissue is a challenge. Long-term systemic administration also comes with concomitant side effects. Thus, local delivery of rifampicin in a carrier to ensure the high local concentration of antibiotic in surgical site after intervention due to infection could be a valuable alternative. However, an ideal platform for local delivery of rifampicin is still lacking. A calcium sulphate/hydroxyapatite (CaS/HA) (Cerament, Bonesupport AB, Sweden) biomaterial was used as a local delivery platform. Here we aimed 1) to evaluate the injectability of CaS/HA hand-mixed with rifampicin at various concentrations up to maximum one daily dose used systemically in clinical practice 2) to test a clinically used and commercially available mixing device containing the biphasic ceramic with rifampicin. Three different concentrations (100 mg, 300 mg and 600 mg) of rifampicin powder (Rifampicin Ebb, Sanofi S.P.A, Italy) diluted in 5 mL of mixing solution (C-TRU, Bonesupport AB, Sweden) were used. Rifampicin solution was mixed to the CaS/HA powder and the injectability of the CaS/HA plus rifampicin composite was evaluated by extruding 250 µL of paste manually through a graduated 1 mL syringe connected to an 18G needle (Ø=1.2 mm, L=4 cm). Mixing was done with a spatula for 30 s at 22°C ±1°C. Total weight of the paste before and after extrusion were measured. To normalize the amount of composite that remained in the needle and syringe tip after injection, the mean of the paste extruded from the syringe at 3 min was calculated for the tested concentrations (normalized value). Injectability (%) was calculated by dividing the weight of the paste extruded from the syringe with normalized value. Each test was repeated for three times at various time points (3, 5, 7 and 9 min). Additionally, 300 mg rifampicin was chosen to mix with the CaS/HA in a commercially available mixing system, which is used clinically.Background
Materials & Methods
This study aimed to investigate the effect of ATDC5 chondrocytes were cultured in insulin-transferrin-selenium medium to induce differentiation. Cells were transfected with pcDNA3.0 plasmids with either a wild-type (WT) or mutated (MUT) Aims
Methods
Bone is a dynamic tissue with a quarter of the trabecular and a fifth of the cortical bone being replaced continuously each year in a complex process that continues throughout an individual’s lifetime. Bone has an important role in homeostasis of minerals with non-stoichiometric hydroxyapatite bone mineral forming the inorganic phase of bone. Due to its crystal structure and chemistry, hydroxyapatite (HA) and related apatites have a remarkable ability to bind molecules. This review article describes the accretion of trace elements in bone mineral giving a historical perspective. Implanted HA particles of synthetic origin have proved to be an efficient recruiting moiety for systemically circulating drugs which can locally biomodulate the material and lead to a therapeutic effect. Bone mineral and apatite however also act as a waste dump for trace elements and drugs, which significantly affects the environment and human health. Cite this article:
The aim of this study was to use diffusion tensor imaging (DTI) to investigate changes in diffusion metrics in patients with cervical spondylotic myelopathy (CSM) up to five years after decompressive surgery. We correlated these changes with clinical outcomes as scored by the Modified Japanese Orthopedic Association (mJOA) method, Neck Disability Index (NDI), and Visual Analogue Scale (VAS). We used multi-shot, high-resolution, diffusion tensor imaging (ms-DTI) in patients with cervical spondylotic myelopathy (CSM) to investigate the change in diffusion metrics and clinical outcomes up to five years after anterior cervical interbody discectomy and fusion (ACDF). High signal intensity was identified on T2-weighted imaging, along with DTI metrics such as fractional anisotropy (FA). MJOA, NDI, and VAS scores were also collected and compared at each follow-up point. Spearman correlations identified correspondence between FA and clinical outcome scores.Aims
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Surgeons and most engineers believe that bone compaction improves implant primary stability without causing undue damage to the bone itself. In this study, we developed a murine distal femoral implant model and tested this dogma. Each mouse received two femoral implants, one placed into a site prepared by drilling and the other into the contralateral site prepared by drilling followed by stepwise condensation.Aims
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