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Type I aortic dissection in a patient with osteogenesis imperfecta.

The previously undescribed association between aortic dissection and osteogenesis imperfecta is reported in a 39-year-old man with known osteogenesis imperfecta, who presented with a type I aortic dissection. His ascending aorta was repaired using a Dacron tube graft under hypothermic circulatory arrest but the patient died 12 h later, following re-dissection around the left coronary ostium resulting in massive myocardial infarction of the left ventricle.

Adult↗

A constant cathodic potential device for faradic stimulation of osteogenesis.

The purpose of this study was to design, develop, and test a device that continuously maintains a constant potential at a cathode with respect to a reference electrode by automatically varying the potential between the cathode and an anode. The ability of the device to maintain a constant cathodic potential with respect to a silver/silver chloride reference electrode is demonstrated in acute testing with a variety of electrodes as well as in chronic testing conducted until battery failure. This constant cathodic potential device permits delivery of current at an optimal cathodic potential for faradic stimulation of osteogenesis which involves a net transfer of charge through biological tissue between, typically, an implanted cathode, the negative electrode where osteogenesis occurs, and either an implanted or a topical anode, the positive electrode required only to complete the electrical circuit. Unlike present devices that maintain a constant direct current between a cathode and an anode but permit potential between said electrodes to vary, this device presents the possible detrimental effects of an undesired electrochemical reaction due to an excessive cathodic potential.

Animals↗

Elevated accumulation of hyaluronate in the tubular bones of osteogenesis imperfecta.

The content and composition of glycosaminoglycans in the tubular bones of osteogenesis imperfecta were compared to those in the tubular bones of age-matched controls. Chondroitin sulfate was the major glycosaminoglycan (70-80% of total) both in the normal and pathological bones, and its level, based on the tissue wet weight, was slightly less in the pathological bones. The composition of chondroitin sulfate disaccharide units in the pathological samples was different from those of the control; a lower proportion of chondroitin 4-sulfate unit. Hyaluronate accounted for at most 7% of total glycosaminoglycans from the normal bones. The hyaluronate content of the pathological bones was 1.5- to 3-fold higher than that of the controls. Glycosaminoglycans have been shown to participate in the formation of a functional supramolecular complex in extracellular matrices. Therefore, it may be postulated that the abnormalities in glycosaminoglycan composition in the tubular bones of osteogenesis imperfecta is implicated in some clinical aspects of this connective tissue disorder such as the bony fragility.

Bone and Bones↗

Effects of bisphosphonates and inorganic pyrophosphate on osteogenesis in vitro.

The bisphosphonates, which are chemically related to pyrophosphate, have been studied extensively both in vivo and in vitro to elucidate their effects on bone tissues and cells. However, because these agents have important effects on bone resorption, the majority of investigations have focused on this area. Few studies regarding direct bisphosphonate effects on bone formation have been carried out in the past and, thus, we chose to use the chick periosteal osteogenesis (CPO) in vitro model system to test the direct effects of pyrophosphate and the bisphosphonates ethane-1-hydroxy-1,1-diphosphate (HEBP) and disodium-1-hydroxy-1-amino-propylidine (APD) on various parameters of osteogenesis in vitro. The data show that the bisphosphonate HEBP inhibits bone mineralization reversibly while APD, at low doses, may actually enhance mineralization of bone. Similarly, pyrophosphate (PPi) will prevent mineralization in CPO cultures. However, CPO cultures can circumvent PPi-mediated blockage of mineralization with longer-term, continuous (10-day) incubation, whereas this does not occur if cultures are incubated continuously with bisphosphonates. Both drugs appear to be able to reverse beta-glycerophosphate-induced changes in alkaline phosphatase activity, but do not appear on their own to regulate the activity of this enzyme. The findings show that in addition to their well-known effects on resorption, bisphosphonates have significant and direct effects on mineralization in bone-forming cultures. Their direct effects on osteoblastic activity and differentiation remain to be determined.

Alkaline Phosphatase↗

Effects of mandibular symphyseal distraction osteogenesis on mandibular structures.

INTRODUCTION: The purpose of this study was to evaluate the effects of mandibular symphyseal distraction osteogenesis on dental and mandibular skeletal structures with a tooth- and bone-borne distraction device. METHODS: The sample comprised 20 patients, ranging in age from 15.8 to 23.3 years (mean, 20.1 +/- 2.3 years) at the start of treatment. The distraction device was activated 1 mm per day. The device was usually maintained in position about 90 days after surgery. Records were obtained at the start of treatment, at the end of distraction (11.4 +/- 2.2 days after surgery), and at follow-up periods (24.1 +/- 4.2 months after surgery). The records included posteroanterior cephalograms and study casts. The data were analyzed statistically by using the repeated measure analysis of variance and paired t test. RESULTS: Posteroanterior cephalometric analysis demonstrated no significant changes in bigonial widths and ramal angles at the end of distraction period. On the other hand, bimolar widths were significantly increased, whereas bicondylar widths were markedly decreased. The dental cast analysis indicated that the maximum amount of increase was found between the mandibular canines, and the widening effect gradually decreased from the mandibular canines to the second molars. The follow-up data confirmed that the treatment results were stable. CONCLUSIONS: The long-term findings indicate that mandibular symphyseal distraction osteogenesis is an efficient nonextraction treatment alternative for mandibular dental crowding to increase mandibular skeletal and dental arch widths.

Adolescent↗

Vitronectin and collagen I differentially regulate osteogenesis in mesenchymal stem cells.

The roles of various soluble factors in promoting the osteogenic differentiation of adult mesenchymal stem cells (MSCs) have been widely studied, but little is known about how the extracellular matrix (ECM) instructs the phenotypic transition between growth and differentiation. To investigate this question, we cultured MSCs on purified vitronectin or type-I collagen, motivated by our earlier tissue engineering work demonstrating that MSC adhesion to polymer scaffolds is primarily mediated by the passive adsorption of these two ECM ligands from serum. Using alkaline phosphatase activity and matrix mineralization as indicators of the early and late stages of osteogenesis, respectively, we report here that both substrates supported differentiation, but the mechanism was substrate dependent. Specifically, osteogenesis on vitronectin correlated with enhanced focal adhesion formation, the activation of focal adhesion kinase (FAK) and paxillin, and the diminished activation of extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3 kinase (PI3K) pathways. By contrast, MSCs on type-I collagen exhibited reduced focal adhesion formation, reduced activation of FAK and paxillin, and increased activation of ERK and PI3K. Inhibition of ERK and FAK blocked mineral deposition on both substrates, suggesting that the observed differences in signaling pathways ultimately converge to the same cell fate. Understanding these mechanistic differences is essential to predictably control the osteogenic differentiation of MSCs and widen their use in regenerative medicine.

Adsorption↗

The effect of incorporating RGD adhesive peptide in polyethylene glycol diacrylate hydrogel on osteogenesis of bone marrow stromal cells.

Advances in tissue engineering require biofunctional scaffolds that can not only provide cells with structural support, but also interact with cells in a biological manner. To achieve this goal, a frequently used cell adhesion peptide Arg-Gly-Asp (RGD) was covalently incorporated into poly(ethylene glycol) diacrylate (PEODA) hydrogel and its dosage effect (0.025, 1.25 and 2.5 mm) on osteogenesis of marrow stromal cells in a three-dimensional environment was examined. Expression of bone-related markers, osteocalcin (OCN) and Alkaline phosphatase (ALP), increased significantly as the RGD concentration increased. Compared with no RGD, 2.5 mm RGD group showed a 1344% increase in ALP production and a 277% increase in OCN accumulation in the medium. RGD helped MSCs maintain cbfa-1 expression when shifted from a two-dimensional environment to a three-dimensional environment. Soluble RGD was found to completely block the mineralization of marrow stromal cells, as manifested by quantitative calcium assay, phosphorus elemental analysis and Von Kossa staining. In conclusion, we have demonstrated that RGD-conjugated PEODA hydrogel promotes the osteogenesis of MSCs in a dosage-dependent manner, with 2.5 mm being optimal concentration.

Alkaline Phosphatase↗

Evaluation of the osteogenesis and biodegradation of porous biphasic ceramic in the human spine.

The histological reports on porous biphasic calcium phosphate ceramic (PBC) in human spine are limited. The osteogenesis and biodegradation of PBC are insufficiently known in human. In present study, the undecalcified histological study was carried out on 20 samples retrieved from posterior spinal fusion in order to reveal the osteogenesis and biodegradation of the PBC in human spine. The quantitative study was performed in 14 samples with sufficient size. Newly formed bone was found in all the samples. More new bone was formed in those samples closely in contact with autogenous bone. The PBC degradation particles were present both in the macrophages and around the tissue. However, those phenomena were highly variable among the samples. New bone formation increased with time and decreased with age. The PBC degradation decreased with age, but it did not differ greatly with time. New bone formation was higher and the residual material was lower in the fusion group than that in non-fusion group. The PBC is a kind of osteoconductive material and do not transform into new bone after a relatively long time. The PBC should be well mixed with the autogenous bone in order to achieve high new bone colonization. The PBC degradation particles and related active phagocytotic activity have been noted.

Absorbable Implants↗

Three-dimensional sutural expansion osteogenesis to expand zygomatic bone: an experimental study.

Sutural expansion osteogenesis was used to extend zygomatic bone three-dimensionally by the formation of new bone in eight goats. A 3 cm incision without osteomy was made in the infraorbital part of the zygomatic bone. The external expansion appliance was then placed on the zygomatic bone. The expansion appliance was activated 10 days after the operation at a rate of 0.9 mm/day for 10 days. The direction could be changed through turning the nuts and moving the brace boards. All the zygomatic bones were expanded anterosuperolaterally and inferolaterally by a mean of 9 mm (range 7.8-11.5mm). The regenerating bone tissues in the distracted sutures were recorded radiographically, clinically, and histologically. The experiment succeeded in expanding the zygoma quickly. The three-dimensional external expansion appliance was simple to operate. The result of sutural expansion osteogenesis is stable and credible, and the method is feasible.

Animals↗

Transplantation of marrow-derived mesenchymal stem cells and platelet-rich plasma during distraction osteogenesis--a preliminary result of three cases.

Clinical results of distraction osteogenesis with transplantation of marrow-derived mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) were reviewed in three femora and two tibiae of the two patients with achondroplasia and one patient with congenital pseudarthrosis of the tibia. MSCs derived from the iliac crest were cultured with osteogenic supplements and differentiated into osteoblast-like cells. PRP, which is known to contain several growth factors and coagulate immediately by a minute introduction of thrombin and calcium, was prepared just before transplantation. Culture-expanded osteoblast-like cells and autologous PRP were injected into the distracted callus with the thrombin-calcium mixture so that the PRP gel might develop within the injected site. Transplantation of MSCs and PRP was done at the lengthening and consolidation period in each patient. The target lengths were obtained in every leg without major complications and the average healing index was 23.0 days/cm (18.8-26.9 days/cm). Although these results are still preliminary, transplantation of osteoblast-like cells and PRP, which seemed to be a safe and minimally invasive cell therapy, could shorten the treatment period by acceleration of bone regeneration during distraction osteogenesis.

Adolescent↗

Intravenous pamidronate treatment of children under 36 months of age with osteogenesis imperfecta.

INTRODUCTION: Bone mineral density (BMD) and fracture rates in children with osteogenesis imperfecta (OI) have been shown to improve with bisphosphonate therapy. There are limited data available on the efficacy of this therapy in children with OI under the age of 3 years. To examine this, we instituted a prospective clinical trial of intravenous bisphosphonate to study safety, feasibility, and efficacy of this therapy. MATERIALS AND METHODS: Nine infants and young children with osteogenesis imperfecta (age range 1-35 months) were treated with intravenous pamidronate. Six had type II OI, two had type I, and one had type IV. Pamidronate was administered in cycles of 3 consecutive days. The total duration of therapy ranged from 11 to 29 months (mean 17 months). RESULTS: During treatment, the mean annualized percent change in total body areal BMD was 25% (range 11-40%). Pamidronate therapy resulted in sustained and significant decreases in serum calcium and bone-specific alkaline phosphatase and in urine calcium/creatinine and NTX/creatinine. Fracture rate in the group decreased from 80 fractures in 111 months before treatment to 25 fractures in 152 months after treatment (P<0.01). Linear growth and weight gain were maintained. Other than fevers in several infants following the initial dose of intravenous bisphosphonate no adverse effects of therapy were noted. CONCLUSIONS: Our data support that intravenous pamidronate therapy is safe, increases BMD, and reduces fracture rates in very young children with OI. Currently, it would seem to be the best available treatment for these children.

Alkaline Phosphatase↗

Differential effects of alendronate treatment on bone from growing osteogenesis imperfecta and wild-type mouse.

Bisphosphonates have been reported to decrease the number of fractures in children with osteogenesis imperfecta (OI). The current study sought to further explore bisphosphonate-associated bone changes in OI by investigating the effects of alendronate (ALN) treatment on bone mechanical and material properties in osteogenesis imperfecta (oim/oim) and wild-type (+/+) mice treated with 26-73 microg kg(-1) day(-1) of ALN for 8 weeks via subcutaneously implanted pumps. Femoral three-point bend tests to evaluate cortical bone were combined with geometric and material density analysis. Cortical and trabecular architecture of metaphyseal bone were histomorphometrically evaluated and material density assessed by quantitative backscattered electron imaging (qBEI). For the cortical oim/oim bone, which revealed principally inferior biomechanical properties compared to +/+ bone, ALN neither improved cortical strength or any other mechanical property, nor affected cortical width (Ct.Wi.) or material density. In contrast, for the +/+ mice, bone strength was enhanced (+22%, P < 0.05) though coupled with increased brittleness (+28%, P < 0.05). This mechanical improvement was associated with an increase in Ct.Wi. (+17.3%, P = 0.02) and a reduction in heterogeneity of cortical mineralization (Ca(Width), -4%, P = 0.04). In the metaphysis, ALN raised cancellous bone volume (BV/TV) significantly in oim/oim as well as in +/+ mice (+97%, P = 0.008 and +200%, P < 0.0001, respectively). This occurred without any change in either material density or trabecular thickness (Tb.Th.) in the oim/oim mice, while in the +/+ mice, material density increased slightly but significantly (+3%, P = 0.004), and Tb.Th. increased by 77% (P < 0.0001). Taken together, these results illustrate the differential effects of ALN on oim/oim vs. +/+ bone, as well as on specific skeletal sites, i.e., cortical vs. trabecular bone. ALN augmented the mechanical, geometrical, and material properties of +/+ cortical and trabecular bone, while the only observable improvement to the oim/oim bone was increased cancellous bone volume. This suggests that in this mouse model of OI, the previously demonstrated bisphosphonate-associated reduction in fractures is primarily attributable to increased metaphyseal bone mass.

Alendronate↗

Bisphosphonate modulates morphological and mechanical properties in distraction osteogenesis through inhibition of bone resorption.

Despite the general clinical acceptance of distraction osteogenesis and much attention to bone formation in this method, little is recognized about activated bone resorption in the regenerated bone. The purpose of this study was to demonstrate the simultaneously activated bone resorption with activated bone formation and to investigate the role and efficacy of bisphosphonate in distraction osteogenesis. Left tibiae of 54 immature rabbits were lengthened for 3 weeks at a rate of 0.7 mm/day after a 1-week lag. Regenerated bone was quantitatively investigated by radiographic bone density, bone histomorphometry, and three-point bending testing. Animals received either vehicle or nitrogen-containing bisphosphonate (N-BP), YM529/ONO5920 at doses of 0.4 mg/kg/w or 0.004 mg/kg/w for 6 weeks. Regenerated bone of the vehicle group showed a radiologically characteristic zone structure containing the osteopenic zones adjacent to the sclerotic zones. The regenerated bone of the 0.4-mg/kg/w group showed no osteopenic zones during the course and eventually became homogeneously radiodense. The bone volume corresponding to the osteopenic zone of this group was 5.6-fold greater compared with that of the vehicle group. The lengthened bone strength of this group was 3.3-fold greater in ultimate force than that of the vehicle group and equivalent to the contralateral tibia. The 0.004-mg/kg/w group had no substantial differences compared with the vehicle group, despite radiological enhancement of the mineralized front as well as somewhat delayed bone resorption. These results demonstrate that not only bone formation but also bone resorption is highly activated in the regenerated bone, implying high bone turnover. Sufficient N-BP caused a notable modulation in morphological properties of the regenerated bone through inhibition of highly activated bone resorption and eventually increased mechanical properties.

Absorptiometry, Photon↗

Purmorphamine induces osteogenesis by activation of the hedgehog signaling pathway.

Previously, a small molecule, purmorphamine, was identified that selectively induces osteogenesis in multipotent mesenchymal progenitor cells. In order to gain insights into the mechanism of action of purmorphamine, high-density oligonucleotide microarrays were used to profile gene expression in multipotent mesenchymal progenitor cells treated with either purmorphamine or bone morphogenetic protein-4 (BMP-4). In contrast to BMP-4 treatment, purmorphamine activates the Hedgehog (Hh) signaling pathway, resulting in the up- and downregulation of its downstream target genes, including Gli1 and Patched. Moreover, the known Hh signaling antagonists, cyclopamine and forskolin, completely block the osteogenesis and Glimediated transcription induced by purmorphamine. These results demonstrate that purmorphamine is a small molecule agonist of Hedgehog signaling, and it may ultimately be useful in the treatment of bone-related disease and neurodegenerative disease.

Alkaline Phosphatase↗

External fixation for distraction osteogenesis.

Distraction osteogenesis methods are indicated in cases of deformity when alternative surgery is not able to produce adequate anatomic restoration and functionality of the foot and ankle. Recent advances in deformity evaluation and techniques of correction may encourage a greater number of surgeons to incorporate distraction osteogenesis into their treatment of complex foot and ankle problems.

Adult↗

Coordinated fibroblast growth factor and heparan sulfate regulation of osteogenesis.

Growth and lineage-specific differentiation constitute crucial phases in the development of stem cells. Control over these processes is exerted by particular elements of the extracellular matrix, which ultimately trigger a cascade of signals that regulate uncommitted cells, by modulating their survival and cell cycle progression, to shape developmental processes. Uncontrolled, constitutive activation of fibroblast growth factor receptors (FGFR) results in bone abnormalities, underlining the stringent control over fibroblast growth factor (FGF) activity that must be maintained for normal osteogenesis to proceed. Mounting evidence suggests that FGF signalling, together with a large number of other growth and adhesive factors, is controlled by the extracellular glycosaminoglycan sugar, heparan sulfate (HS). In this review, we focus on FGF activity during osteogenesis, their receptors, and the use of HS as a therapeutic adjuvant for bone repair.

Animals↗

Effect of platelet-rich-plasma on cranial distraction osteogenesis in sheep: preliminary clinical and radiographic results.

The purpose of this study was to investigate the effect of platelet-rich-plasma (PRP) on cranial distraction osteogenesis. Standardized calvaria critical size defects (6 cm x 5 cm) were created in 16 adult female sheep. Bifocal cranial transport distraction osteogenesis with autogenous free calvaria bone grafts (2 cm x 4 cm) was performed at a rate of 1mm once daily to a total of 30 mm. The 16 sheep involved in the experiment were randomly divided into four groups, four animals in each: Group 1 (no PRP, latency 5 days); Group 2 (no PRP, latency 0 day), Group 3 (PRP, latency 5 days) and Group 4 (PRP, latency 0 day). After a consolidation phase of 6 weeks, the animals were sacrificed and specimens harvested for conventional radiological and 3D quantitative computer tomographic (3D-QCT) assessment. New bone was generated in the distraction zone in all groups. There were significantly (P < 0.05) higher densities in the proximal region of the distraction regenerate in Group 4 (PRP, latency 0 day) compared to Group 2. However, no significant differences in mean density of the total distraction regenerate were found, neither in volume of the bony regenerate between the experimental groups. This study showed that PRP only had an effect on bone regeneration if active distraction was started immediately after application of PRP in the distraction gap.

Analysis of Variance↗

A retrospective study of the potential complications during alveolar distraction osteogenesis in 55 patients.

The aim of this retrospective study was to analyse the outcome of alveolar distraction osteogenesis for the correction of vertical defects in a large series of 55 cases. The existing bone deficiencies were secondary to atrophy after periodontal disease or tooth extraction. The overall success rate of this technique was 89.1%. The complications presented during treatment were divided into minor (no effect on final result, but immediate intervention required) 14/55 patients (25.4%), and major (lead to technique failure) 6/55 patients (10.9%). The frequency of minor complications was 8/27 in the anterior maxillary region, 1/27 in the anterior mandibular region and 15/27 in the posterior mandibular region. The frequency of major complications was 5/6 in the posterior mandibular region and 1/6 in the anterior maxillary region. The mean alveolar height achieved was 6mm. The overall rate was 36.3%. On the basis of these results it was concluded that alveolar distraction osteogenesis is an effective technique to treat vertical alveolar ridge deficiencies.

Adult↗