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woven bone [keywords]
- Osteocyte expression of caspase-3, COX-2, IL-6 and sclerostin are spatially and temporally associated following stress fracture initiation. [Journal Article]
- Bonekey Rep 2014.:571.
Stress fractures (SFxs) are debilitating injuries and exact mechanisms that initiate their repair incompletely understood. We hypothesised that osteocyte apoptosis and expression of cytokines and proteins such as sclerostin, VEGF, TGF-β, COX-2 and IL-6 were early signalling events to facilitate the formation of periosteal woven bone and recruitment of osteoclast precursors to the site of remodelling. A SFx was created in the right ulna of mature female wistar rats using cyclic end loading. Rats were killed 1, 4 and 7 days after loading (n=5 per group). Standard histological staining was used to examine SFx morphology and immunohistochemistry to detect the localisation of these proteins and in situ hybridisation to detect mRNA along the SFx line or gene expression to quantify the target genes. Unloaded ulnae served as controls. The labelling index of caspase-3, COX-2 and IL-6 was significantly elevated in the region of SFxs at all time points compared with controls (P<0.001). In addition, the labelling index of sclerostin protein was significantly reduced in osteocytes adjacent to the SFx region when compared with controls at all three time points (P<0.001). Both VEGF and TGF-β expressions were only localised in the woven bone. These data reinforce the involvement of osteocyte apoptosis in the healing of fatigue damage in bone, and demonstrate that local regulation of sclerostin, COX-2 and IL-6 are important signalling events associated with new bone formation and SFx remodelling.
- Sensory innervation around immediately vs. delayed loaded implants: a pilot study. [JOURNAL ARTICLE]
- Int J Oral Sci 2014 Sep 12.
Although neurophysiological and psychophysical proof of osseoperception is accumulating, histomorphometric evidence for the neural mechanisms of functional compensation following immediate and delayed implant loading is still lacking. For this randomized split-mouth study, six mongrel dogs randomly received one of four treatment protocols at 36 implant-recipient sites over 16 weeks (third maxillary incisor, third and fourth mandibular premolar): immediate implant placement and immediate loading (IIP+IL); delayed implant placement and delayed loading (DIP+DL); delayed implant placement and immediate loading (DIP+IL); and natural extraction socket healing (control). Histomorphometry was performed in the peri-implant bone and soft tissues within 300 µm around the implants. Immunocytochemistry and transmission electron microscopy were used to confirm the presence of neural structures and to reveal their ultrastructural characteristics, respectively. Myelinated nerve fibres densely populated the peri-implant crestal gingival and apical regions, although they were also identified in the woven bone and in the osteons near the implant threads. Compared with the control group in the mandible, the group that received IIP+IL showed a higher innervation (in N⋅mm(-2), 5.94±1.12 vs. 3.15±0.63, P<0.001) and smaller fibre diameter (in µm, 1.37±0.05 vs. 1.64±0.13, P=0.016), smaller axon diameter (in µm, 0.89±0.05 vs. 1.24±0.10, P=0.009) and g-ratio (0.64±0.04 vs. 0.76±0.05, P<0.001) in the middle region around the implants. Compared with DIP+IL in the mandible, IIP+IL had a higher nerve density (in N⋅mm(-2), 13.23±2.54 vs. 9.64±1.86, P=0.027), greater fibre diameter (in µm, 1.32±0.02 vs. 1.20±0.04, P=0.021), greater axon diameter (in µm, 0.92±0.01 vs. 0.89±0.03, P=0.035) and lower g-ratio (0.69±0.01 vs. 0.74±0.01, P=0.033) in the apical region around the implants. It may be assumed that the treatment protocol with IIP+IL is the preferred method to allow optimized peri-implant re-innervation, but further functional measurements are still required.International Journal of Oral Science advance online publication, 12 September 2014; doi:10.1038/ijos.2014.53.
- Microradiographic and histological evaluation of the bone-screw and bone-plate interface of orthodontic miniplates in patients. [JOURNAL ARTICLE]
- Eur J Orthod 2014 Sep 1.
Summary OBJECTIVES: To describe the tissue reactions at the bone-titanium interface of orthodontic miniplates in humans.Forty-two samples, consisting of tissue fragments attached or not to miniplates or their fixation screws, were collected from 24 orthodontic patients treated with miniplate anchorage, at the time of removal of their miniplates. The samples were embedded in methylmethacrylate and cut into undecalcified sections which were submitted to microradiographic analysis. The sections were also stained and examined under ordinary light.Three types of reactions were observed both on the histological sections and on the microradiographs. 1. The majority of the stable miniplates were easy to remove (34/42). The tissue samples collected consisted mainly in mature lamellar bone with some medullary spaces containing blood vessels, 2. two screws were highly osseointegrated and required the surgeon to remove them by trephining (2/42). They were surrounded by bone tissue which extended to the miniplate. The histological features were similar to the previous group, though the bone-screw contact was higher, and 3. in six samples obtained after unstable miniplate removal during the treatment, we observed either some woven bone trabeculae or loose connective tissue, without any histological sign of inflammation.For evident ethical reasons, our data were limited by the size of the tissue fragments and the limited number of patients and variety of clinical presentations. The healing reactions consisted mainly in mature lamellar bone tissue sparsely in contact with the screw or the miniplate, with signs of a moderate remodelling activity.
- Impaired Bone Resorption and Woven Bone Formation Are Associated with Development of Osteonecrosis of the Jaw-Like Lesions by Bisphosphonate and Anti- Receptor Activator of NF-κB Ligand Antibody in Mice. [JOURNAL ARTICLE]
- Am J Pathol 2014 Aug 27.
Drug-induced osteonecrosis of the jaw (ONJ) is a detrimental intraoral lesion that often occurs after dental-related interventions in patients undergoing treatment with bisphosphonates or denosumab, the neutralizing human anti-receptor activator of NF-κB ligand (RANKL) antibody (Ab). The cause of ONJ by these drugs has been speculated to their direct effects on osteoclasts. However, the extent to which osteoclasts contribute to ONJ pathogenesis remains controversial. Herein, by using a tooth-extraction mouse model with i.v. administration of mouse anti-RANKL Ab or zoledronate (ZOL), we show that unresorbed bone due to impaired formation or suppressed functions of osteoclasts, respectively, is associated with ONJ development. After tooth extraction, ONJ-like lesions developed 50% in the anti-RANKL Ab-treated mice and 30% in the ZOL-treated mice. Nonviable and unresorbed bone was found more in anti-RANKL Ab-treated mice compared with mice receiving ZOL. All mice receiving anti-RANKL Ab had an undetectable tartrate-resistant acid phosphatase (TRAP) level in the serum and no TRAP-positive osteoclasts at the extracted sockets, whereas ZOL-treated mice had a decreased TRAP level without altering the numbers of TRAP-positive osteoclasts. Interestingly, the absence of newly formed woven bone in the extracted sockets was evident in ONJ-like lesions from both anti-RANKL Ab- and ZOL-treated mice. Our study suggests that the lack of osteoclasts' bone-resorptive functions by these drugs and suppression of woven bone formation after dental trauma may be associated with ONJ development.
- Protuberant Fibro-osseous Lesions of the Temporal Bone: Two Additional Case Reports. [JOURNAL ARTICLE]
- Am J Surg Pathol 2014 Aug 12.
The most commonly encountered fibro-osseous lesions of the skull bone are fibrous dysplasia and ossifying fibroma. Two cases of a unique "protuberant fibro-osseous lesion of the temporal bone" were first described by Selesnick and colleagues in 1999, and 2 further cases were reported in 2010 under the name "Bullough lesion". We recently found 2 new cases of this rare entity. Two Korean female patients aged 70 and 54 years presented with slow growing postauricular masses without pain or tenderness for 6 and 7 years, respectively. Computed tomography revealed a 2.9 cm calcified mass in the temporal bone of the first patient, and a 5.5 cm enhancing mass with internal cartilaginous matrix in the temporal bone of the second patient. Intramedullary or intracranial extension was not found in either case, and en bloc removals were performed. Microscopically, multiple round to oval osseous islands were scattered throughout the bland fibrous stroma in both cases. The osseous islands varied in size and were lamellar or woven, without osteoblastic rimming, and surrounded by fibroblastic bands. Neither patient has shown evidence of postoperative recurrence for 18 months. The location, histology, and clinical course of these 2 cases were identical to the 4 cases previously reported, although age and sex varied. The lesions were tested for the R201H mutation in the GNAS gene, which is present in fibrous dysplasia. No mutations were found, suggesting a different genetic background for these lesions.
- Electrospun polyurethane/hydroxyapatite bioactive Scaffolds for bone tissue engineering: The role of solvent and hydroxyapatite particles. [Journal Article]
- J Mech Behav Biomed Mater 2014 Nov.:95-110.
Polyurethane (PU) is a promising polymer to support bone-matrix producing cells due to its durability and mechanical resistance. In this study two types of medical grade poly-ether urethanes Z3A1 and Z9A1 and PU-Hydroxyapatite (PU-HA) composites were investigated for their ability to act as a scaffold for tissue engineered bone. PU dissolved in varying concentrations of dimethylformamide (DMF) and tetrahydrofuran (THF) solvents were electrospun to attain scaffolds with randomly orientated non-woven fibres. Bioactive polymeric composite scaffolds were created using 15wt% Z3A1 in a 70/30 DMF/THF PU solution and incorporating micro- or nano-sized HA particles in a ratio of 3:1 respectively, whilst a 25wt% Z9A1 PU solution was doped in ratio of 5:1. Chemical properties of the resulting composites were evaluated by FTIR and physical properties by SEM. Tensile mechanical testing was carried out on all electrospun scaffolds. MLO-A5 osteoblastic mouse cells and human embryonic mesenchymal progenitor cells, hES-MPs were seeded on the scaffolds to test their biocompatibility and ability to support mineralised matrix production over a 28 day culture period. Cell viability was assayed by MTT and calcium and collagen deposition by Sirius red and alizarin red respectively. SEM images of both electrospun PU scaffolds and PU-HA composite scaffolds showed differences in fibre morphology with changes in solvent combinations and size of HA particles. Inclusion of THF eliminated the presence of beads in fibres that were present in scaffolds fabricated with 100% DMF solvent, and resulted in fibres with a more uniform morphology and thicker diameters. Mechanical testing demonstrated that the Young׳s Modulus and yield strength was lower at higher THF concentrations. Inclusion of both sizes of HA particles in PU-HA solutions reinforced the scaffolds leading to higher mechanical properties, whilst FTIR characterisation confirmed the presence of HA in all composite scaffolds. Although all scaffolds supported proliferation of both cell types and deposition of calcified matrix, PU-HA composite fibres containing nano-HA enabled the highest cell viability and collagen deposition. These scaffolds have the potential to support bone matrix formation for bone tissue engineering.
- Modifications to Nano- and Microstructural Quality and the Effects on Mechanical Integrity in Paget's Disease of Bone. [JOURNAL ARTICLE]
- J Bone Miner Res 2014 Aug 12.
Paget's disease of bone (PDB) is the second most common bone disease mostly developing after 50 years of age at one or more localized skeletal sites; it is associated with severely high bone turnover, bone enlargement, bowing/deformity, cracking and pain. Here, to specifically address the origins of the deteriorated mechanical integrity, we use a cohort of control and PDB human biopsies to investigate multi-scale architectural and compositional modifications to the bone structure (i.e., bone quality) and relate these changes to mechanical property measurements to provide further insight into the clinical manifestations (i.e., deformities and bowing) and fracture risk caused by PDB. Here, at the level of the collagen and mineral (i.e., nanometer length-scale), we find a 19% lower mineral content and lower carbonate-to-phosphate ratio in PDB, which accounts for the 14% lower stiffness and 19% lower hardness promoting plastic deformation in pathological bone. At the microstructural scale, trabecular regions are known to become densified, while cortical bone loses its characteristic parallel-aligned osteonal pattern, which is replaced with a mosaic of lamellar and woven bone. While we find this loss of anisotropic alignment produces a straighter crack path in mechanically loaded PDB cases, cortical fracture toughness appears to be maintained due to increased plastic deformation. Clearly, the altered quality of the bone structure in PDB affects the mechanical integrity leading to complications such as bowing, deformities, and stable cracks called fissure fractures associated with this disease. While the lower mineralization and loss of aligned Haversian structures do produce a lower modulus tissue, which is susceptible to deformities, our results indicate that the higher levels of plasticity may compensate for the lost microstructural features and maintain the resistance to crack growth. © 2014 American Society for Bone and Mineral Research.
- Novel intramedullary-fixation technique for long bone fragility fractures using bioresorbable materials. [Journal Article]
- PLoS One 2014; 9(8):e104603.
Almost all of the currently available fracture fixation devices for metaphyseal fragility fractures are made of hard metals, which carry a high risk of implant-related complications such as implant cutout in severely osteoporotic patients. We developed a novel fracture fixation technique (intramedullary-fixation with biodegradable materials; IM-BM) for severely weakened long bones using three different non-metallic biomaterials, a poly(l-lactide) (PLLA) woven tube, a nonwoven polyhydroxyalkanoates (PHA) fiber mat, and an injectable calcium phosphate cement (CPC). The purpose of this work was to evaluate the feasibility of IM-BM with mechanical testing as well as with an animal experiment. To perform mechanical testing, we fixed two longitudinal acrylic pipes with four different methods, and used them for a three-point bending test (N = 5). The three-point bending test revealed that the average fracture energy for the IM-BM group (PLLA + CPC + PHA) was 3 times greater than that of PLLA + CPC group, and 60 to 200 times greater than that of CPC + PHA group and CPC group. Using an osteoporotic rabbit distal femur incomplete fracture model, sixteen rabbits were randomly allocated into four experimental groups (IM-BM group, PLLA + CPC group, CPC group, Kirschner wire (K-wire) group). No rabbit in the IM-BM group suffered fracture displacement even under full weight bearing. In contrast, two rabbits in the PLLA + CPC group, three rabbits in the CPC group, and three rabbits in the K-wire group suffered fracture displacement within the first postoperative week. The present work demonstrated that IM-BM was strong enough to reinforce and stabilize incomplete fractures with both mechanical testing and an animal experiment even in the distal thigh, where bone is exposed to the highest bending and torsional stresses in the body. IM-BM can be one treatment option for those with severe osteoporosis.
- Runx2-smad signaling impacts the progression of tumor-induced bone disease. [JOURNAL ARTICLE]
- Int J Cancer 2014 Jul 23.
Runx2, a master regulator of osteogenesis, is abnormally expressed in advanced prostate cancer. Here, we addressed Runx2 contribution to formation of prostate cancer-related osteolytic and osteoblastic bone lesions by mediating TGFβ/BMP signaling through direct interaction with Smads. Further, we examined involvement of the Runx2-Smad complex in mediating tumor growth and distal metastasis. To identify Runx2-Smad-specific mechanisms of prostate tumor activity in bone, we generated PC3 prostate cancer cell lines expressing Runx2-WT or one of two mutant proteins (Runx2-HTY and Runx2-ΔC) that each disrupt the Runx2-Smad interaction, either directly through a point mutation or by deletion of the functional C-terminus, respectively. Intratibial tumors generated from these cells revealed that Runx2-WT-expressing cells resulted in predominantly osteolytic disease, whereas cells expressing mutant proteins exhibited tumors with mixed osteolytic/osteoblastic lesions. Extent of bone loss and woven bone formation was assessed by radiography and micro-computed tomography. Bioluminescent imaging showed the presence of labeled prostate cancer cells in the lung at the latest time point examined, with Runx2-WT group exhibiting increased incidence of tumor cells in lung. Notably, disruption of the Runx2-Smad interaction significantly reduced incidence and size of lung tumors. Altered expression of Runx2 target genes involved in invasion, growth, adhesion and metastasis supported our findings. Thus, our studies demonstrate that Runx2 in prostate cancer cells plays a significant role in intratibial prostate cancer-related tumor growth and bone loss through mechanisms mediated by the Runx2-Smad signaling pathway. This work expands upon the potential importance of Runx2 as a therapeutic target in cancer.
- The effect of implant diameter on osseointegration utilizing simplified drilling protocols. [JOURNAL ARTICLE]
- Clin Oral Implants Res 2013 Oct 8.
To observe and to compare histologically and histomorphometrically, the combined effect of drilling sequence and implant diameter in vivo.A total of 72 alumina-blasted and acid-etched Ti-6Al-4V implants with three different diameters (3.75, 4.2, and 5 mm, n = 24 for each group) were placed in the right and left tibiae of 12 beagle dogs. Within the same diameter group, half of the implants were inserted after a simplified drilling procedure (pilot drill + final diameter drill) on one tibia and the other half were placed using the conventional drilling procedure on the other tibia. After 1 week, half of the animals (n = 6) were sacrificed, and the other half was sacrificed after 5 weeks (n = 6). The retrieved bone-implant samples were subjected to non-decalcified histologic sectioning, and the bone-to-implant contact (BIC) and the bone area fraction occupancy (BAFO) were analyzed. Primary statistical analysis used a mixed model analysis of variance with significance level set at P < 0.05.Histologic observation showed that at 1 week, immature woven bone formed in vicinity of the implant, whereas at 5 weeks, the woven bone was replaced by lamellar bone, which formed in proximity with the implant. Histomorphometrically, the simplified technique was associated with significantly greater BIC and BAFO after 1 week. Differences between techniques were not longer apparent after 5 weeks, but BAFO was inversely and significantly associated with implant diameter at that time.The simplified technique did not impair either early or late bone formation for any tested implant diameter; however, wider diameters were associated with less bone formation at longer healing times for both techniques.