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Biomedical subjects

Ralph Müller

Publications and source records attributed to Ralph Müller.

At least 37 records · Page 2Linked to original sources
PubMed2005

Intermittently administered parathyroid hormone 1-34 reverses bone loss and structural impairment in orchiectomized adult rats.

Male osteoporosis is emerging as a central theme in bone research. As in females, hypogonadism appears as a principal risk factor in men that leads to bone loss and increased fracture incidence. Intermittently administered parathyroid hormone (PTH) reverses bone loss in sex hormone-deprived women and female animals and increases bone mass in elderly men and normal male animals. This study was carried out to assess whether the PTH anabolic activity is also effective in adult castrated males and to gain insight into the underlying tissue processes. Bilateral orchiectomy (ORX) or sham-ORX was performed in 13-week old rats. Five weeks later, the ORX rats were treated intermittently with human PTH(1-34), 80 microg/kg/day or vehicle for 6 weeks. Femora were evaluated by quantitative micro-computed tomography followed by dynamic histomorphometry. The trabecular bone volume density showed 40% and 56% ORX-induced loss in the distal metaphysis at 6 weeks and 12 weeks post-ORX, respectively. PTH(1-34) induced supraphysiologic recovery of this bone loss (155% recovery) consequent to a vast increase in trabecular thickness (174% over sham-ORX controls) and a partial reversal (62%) of the decrease in trabecular number. As compared with the results in 12-week, orchiectomized vehicle-administered rats, the PTH(1-34) treatment induced a significant decrease in osteoclast number (20%) and twofold increase in bone formation rate. While ORX did not affect the femoral diaphysis, PTH(1-34) induced marked cortical thickening via the stimulation of endosteal mineral appositional rate (154% over ORX rats). These data portray PTH(1-34) as a highly potent bone anabolic agent in adult ORX rats, mainly by increasing both the trabecular and cortical thicknesses through its effect on osteoblasts and osteoclasts. The adult ORX rat is useful for investigating the processes involved in bone anabolic activity in castrated osteoporotic males and for the development of bone anabolic agents for treating this condition.

Animals↗
PubMed2005

Leaky ribosomal scanning in mammalian genomes: significance of histone H4 alternative translation in vivo.

Like alternative splicing, leaky ribosomal scanning (LRS), which occurs at suboptimal translational initiation codons, increases the physiological flexibility of the genome by allowing alternative translation. Comprehensive analysis of 22 208 human mRNAs indicates that, although the most important positions relative to the first nucleotide of the initiation codon, -3 and +4, are usually such that support initiation (A-3 = 42%, G-3 = 36% and G+4 = 47%), only 37.4% of the genes adhere to the purine (R)-3/G+4 rule at both positions simultaneously, suggesting that LRS may occur in some of the remaining (62.6%) genes. Moreover, 12.5% of the genes lack both R-3 and G+4, potentially leading to sLRS. Compared with 11 genes known to undergo LRS, 10 genes with experimental evidence for high fidelity A+1T+2G+3 initiation codons adhered much more strongly to the R-3/G+4 rule. Among the intron-less histone genes, only the H3 genes adhere to the R-3/G+4 rule, while the H1, H2A, H2B and H4 genes usually lack either R-3 or G+4. To address in vivo the significance of the previously described LRS of H4 mRNAs, which results in alternative translation of the osteogenic growth peptide, transgenic mice were engineered that ubiquitously and constitutively express a mutant H4 mRNA with an A+1T+1 mutation. These transgenic mice, in particular the females, have a high bone mass phenotype, attributable to increased bone formation. These data suggest that many genes may fulfill cryptic functions by LRS.

Animals↗
PubMed2005

Design and implementation of a novel mechanical testing system for cellular solids.

Cellular solids constitute an important class of engineering materials encompassing both man-made and natural constructs. Materials such as wood, cork, coral, and cancellous bone are examples of cellular solids. The structural analysis of cellular solid failure has been limited to 2D sections to illustrate global fracture patterns. Due to the inherent destructiveness of 2D methods, dynamic assessment of fracture progression has not been possible. Image-guided failure assessment (IGFA), a noninvasive technique to analyze 3D progressive bone failure, has been developed utilizing stepwise microcompression in combination with time-lapsed microcomputed tomographic imaging (microCT). This method allows for the assessment of fracture progression in the plastic region, where much of the structural deformation/energy absorption is encountered in a cellular solid. Therefore, the goal of this project was to design and fabricate a novel micromechanical testing system to validate the effectiveness of the stepwise IGFA technique compared to classical continuous mechanical testing, using a variety of engineered and natural cellular solids. In our analysis, we found stepwise compression to be a valid approach for IGFA with high precision and accuracy comparable to classical continuous testing. Therefore, this approach complements the conventional mechanical testing methods by providing visual insight into the failure propagation mechanisms of cellular solids.

Aluminum↗
PubMed2005

In vivo bone regeneration with injectable calcium phosphate biomaterial: a three-dimensional micro-computed tomographic, biomechanical and SEM study.

This in vivo study investigated the efficiency of an injectable calcium phosphate bone substitute (IBS) for bone regenerative procedures through non-destructive three-dimensional (3D) micro-tomographic (microCT) imaging, biomechanical testing with a non-destructive micro-indentation technique and 2D scanning electron microscopy (SEM) analysis. The injectable biomaterial was obtained by mixing a biphasic calcium phosphate (BCP) ceramic mineral phase and a cellulosic polymer. The BCP particles were 200-500 microm or 80-200 microm in diameter. The injectable material was implanted for 6 weeks into critical-sized bone defects at the distal end of rabbit femurs. Extensive new bone apposition was noted with both 2D and 3D techniques. Micro-CT showed that newly formed bone was in perfect continuity with the trabecular host bone structure and demonstrated the high interconnectivity of the restored bone network. For both IBS formulations, SEM and microCT gave very close measurements. The only detected significant difference concerned the amount of newly formed bone obtained with IBS 80-200 that appeared significantly higher with microCT analysis than with SEM (p=0.00007). Student t-tests did not show any significant difference in the amount of newly formed bone and remaining ceramic obtained from microCT analysis or SEM. Regression analysis showed satisfactory correlation between both the amount of newly formed bone and remaining ceramic obtained from microCT or SEM. For IBS 200-500, the newly formed bone rate inside the defect was 28.0+/-5.2% with SEM and yield strength of the samples was 18.8+/-5.4 MPa. For IBS 80-200, the newly formed bone rate inside the defect was 31.7+/-5.1% with SEM and yield strength of the samples was 26.8+/-4.5 MPa. Yield strength appeared well correlated with the amount of newly formed bone, specially observed with microCT. This study showed the ability of non-destructive techniques to investigate biological and mechanical aspects of bone replacement with injectable biomaterials.

Animals↗
PubMed2005

Prediction of fracture callus mechanical properties using micro-CT images and voxel-based finite element analysis.

Assessment of fracture healing is a common problem in orthopaedic practice and research. To determine the effectiveness of certain treatments, drugs, mechanical loads, or rehabilitation regimes, the strength of the fracture callus must be determined. Both clinically and experimentally, there is a need to noninvasively and quantitatively evaluate fracture callus quality during healing. The objective of this study was to develop a method to assess fracture stiffness using micro-computed tomography (micro-CT) and finite element analysis. The method was developed and validated with plastic phantoms of various cross sections and known material properties, tested experimentally in four-point bending and torsion. The method was then applied to fractured rat femurs after 3 and 4 weeks of healing tested experimentally in torsion (50 femurs total). Micro-CT scans were made of the fracture calluses to determine three-dimensional geometry and material properties for the finite element models. Experimentally measured torsional rigidities were compared to finite element solutions. Finite element model predictions of callus rigidity correlated significantly better with experimental torsional rigidity than other common measures of healing progress such as callus area, bone mineral density, or area moment of inertia. Using FEA to predict mechanical properties of the callus could prove to be a useful tool in fracture-healing studies.

Animals↗
PubMed2004

Long-term prediction of three-dimensional bone architecture in simulations of pre-, peri- and post-menopausal microstructural bone remodeling.

The mechanical behavior of trabecular bone depends on the internal bone structure. It is generally accepted now that the trabecular bone structure is a result of a load adaptive bone remodeling. The mathematical laws that relate bone remodeling to the local state of stress and strain, however, are still under investigation. The aim of this project was to investigate if changes in the trabecular architecture as observed with age-related bone loss and osteoporosis can be predicted from a computer model that simulates bone resorption after hormone depletion based on realistic models of trabecular microstructure using micro-computed tomography (muCT). A compact desktop muCT providing a nominal isotropic resolution of 14 mum was used to measure two groups of seven trabecular bone specimens from pre-menopausal and post-menopausal women respectively. A novel algorithm was developed to simulate age-related bone loss for the specimens in the first group. The algorithm, also referred to as simulated bone atrophy (SIBA), describes a truly three-dimensional approach and is based directly on cellular bone remodeling with an underlying realistic time frame. Bone resorption is controlled by osteoclastic penetration depth and bone formation is governed by the efficiency level of the osteoblasts. The simulation itself describes an iterative process with a cellular remodeling cycle of 197 days. Activation frequency is controllable and can be adjusted for the different phases of pre-, peri- and post-menopause. For our simulations, osteoblastic and osteoclastic activities were in balance until the onset of menopause, set to be at the age of 50 years. In that period, the structure remained almost constant. After the onset of menopause an imbalance in the cell activities was modeled resulting in a net bone loss. The doubling of the activation frequency in the peri-menopausal phase caused a pronounced loss. Using advanced animation tools and quantitative bone morphometry, the changes in bone architecture associated with the bone loss were monitored over an average observation time of 43 years until the age of 80 years. In that time, bone volume density decreased monotonously with the progression of the simulation for all specimens. Right after the onset of menopause, bone was lost fast, where with the progression of age losses slowed down. The structures at the end-point of the simulations were then compared qualitatively and quantitatively to the structures of the post-menopausal group with all morphometric indices being within a narrow margin of error. These results suggest the feasibility of transforming "normal" to "osteopenic" bone on a microstructural level yielding in realistic bone models similar in appearance as well as in structural behavior if compared to a post-menopausal group of women.

Aged↗
PubMed2004

Intermittent ibandronate preserves bone quality and bone strength in the lumbar spine after 16 months of treatment in the ovariectomized cynomolgus monkey.

UNLABELLED: The dose-dependent effect of ibandronate treatment on bone mass and architecture was assessed in a large animal study of OVX monkeys using microCT for quantitative bone morphometry and biomechanical testing for measures of bone strength. The study showed that intermittent ibandronate preserved lumbar spine bone quality and strength in these animals after 16 months of treatment. INTRODUCTION: Ibandronate is a bisphosphonate, which is a class of compounds that, in pharmacologically active doses, not only suppresses bone resorption and turnover but also prevents loss of bone mass and strength in the ovariectomized (OVX) rat. MATERIALS AND METHODS: We evaluated the effects of ibandronate on bone mass and architecture in the OVX cynomolgus macaque. Sixty-one adult female macaques were divided into five groups (N = 11-15): sham control, OVX control, and OVX low- (10 microg/kg), medium- (30 microg/kg), and high- (150 microg/kg) dose ibandronate. Treatment was administered by intravenous bolus injection every 30 days for 16 months starting at ovariectomy. This dosing schedule is equivalent to a 3-monthly dosing regimen in human subjects over 4 years. Animals were killed at the conclusion of the study, and excised bone specimens of the first lumbar vertebra (L1) were evaluated for quantitative bone densitometry, morphometry, and mechanical properties. Architectural parameters were assessed by microCT including direct 3D bone morphometry. A measure of specimen strength was obtained using destructive compression testing. RESULTS AND CONCLUSIONS: A significant loss of bone mass and related changes in bone architecture after ovariectomy resulted in a reduction of whole bone strength as expressed by high correlations between architectural and mechanical properties. In this analysis, BMC was the best single predictor of whole bone strength (r2 = 67%). Nevertheless, including architectural indices in a multiple linear regression analysis increased that prediction to 88%. With respect to the treatment, the medium- and high-dose groups were not significantly different from the sham group for all bone mineral and structural parameters. Additionally, significant differences were seen for all measured parameters between the high-dose group and the OVX group, and for some parameters, between the medium-dose group and the OVX group. Intermittent ibandronate treatment effectively and dose-dependently prevented bone loss, architectural deterioration, and strength reduction in the lumbar spine of OVX monkeys.

Animals↗
PubMed2004

Synthetic extracellular matrices for in situ tissue engineering.

Cell interactions with the extracellular matrix play important roles in guiding tissue morphogenesis. The matrix stimulates cells to influence such things as differentiation and the cells actively remodel the matrix via local proteolytic activity. We have designed synthetic hydrogel networks that participate in this interplay: They signal cells via bound adhesion and growth factors, and they also respond to the remodeling influence of cell-associated proteases. Poly(ethylene glycol)-bis-vinylsulfone was crosslinked by a Michael-type addition reaction with a peptide containing three cysteine residues, the peptide sequence being cleavable between each cysteine residue by the cell-associated protease plasmin. Cells were able to invade gel networks that contained adhesion peptides and were crosslinked by plasmin-sensitive peptides, while materials lacking either of these two characteristics resisted cell infiltration. Incorporated bone morphogenetic protein-2 (BMP-2) induced bone healing in a rat model in materials that were both adhesive and plasmin-sensitive, while materials lacking plasmin sensitivity resisted formation of bone within the material. Furthermore, when a heparin bridge was incorporated as a BMP-2 affinity site, mimicking yet another characteristic of the extracellular matrix, statistically improved bone regeneration was observed.

Absorbable Implants↗
PubMed2004

New approach to quantifying developmental variation in the dentition using serial microtomographic imaging.

Dental morphogenesis and cellular differentiation are expressed in the fully formed tooth by the topography of the dentin-enamel junction and outer enamel surface. These boundaries can be differentiated using a variety of imaging systems. In this study, we used serial microCT imaging to provide accurate 3D reconstructions of developing lower human second deciduous molars. These were used to quantify the volume of enamel and dentin of individual cusps in relation to basal crown height. As growth and differentiation proceed apically, the spatial orientation of cusp tips and their bases were used to estimate their order of initiation and coalescence. We found that the order of coalescence differed from the order of initiation. We also found that dentin cusp height and volume as well as rate and quantity of enamel apposition varied along mesio-distal and bucco-lingual axes, and were independent of order of initiation and duration of growth. These results demonstrate that the potential for variation in crown size and form is maintained throughout development. We propose that the microCT model developed in this study constitutes a new approach for the investigation of developmental variation and its contribution to phylogenetic variation expressed in crown form and size.

Dental Enamel↗
PubMed2004

Osteogenic growth peptide modulates fracture callus structural and mechanical properties.

The osteogenic growth peptide (OGP) is a key factor in the mechanism of the systemic osteogenic response to local bone marrow injury. Recent histologic studies have shown that OGP enhances fracture healing in experimental animals. To assess the effect of systemically administered OGP on the biomechanical and quantitative structural properties of the fracture callus, the present study used an integrated approach to evaluate the early stages (up to 4 weeks) of healing of unstable mid-femoral fractures in rats, which included biomechanical, micro-computed tomographic (microCT) and histomorphometric measurements. During the first 3 weeks after fracture, all the quantitative microCT parameters increased in the OGP- and vehicle-treated animals alike. After 4 weeks, the volume of total callus, bony callus, and newly formed bone was approximately 20% higher in animals administered with OGP, consequent to a decrease in the controls. The 4-week total connectivity was 46% higher in the OGP-treated animals. At this time, bridging between the fracture ends by newly formed bone was observed predominantly in the OGP-treated fractures. After 3 and 4 weeks, the OGP-treated animals showed higher biomechanical toughness of the fracture callus as compared to the PBS controls. Significant correlations between structural and biomechanical parameters were restricted to the OGP-treated rats. These data imply that the osteogenic effect of OGP results in enhanced bridging across the fracture gap and consequently improved function of the fracture callus. Therefore, OGP and/or its derivatives are suggested as a potential therapy for the acceleration of bone regeneration in instances of fracture repair and perhaps other bone injuries.

Animals↗
PubMed2004

Time-lapsed microstructural imaging of bone failure behavior.

Many bones within the axial and appendicular skeleton are subjected to repetitive loading during the course of ordinary daily activities. If this loading is of sufficient magnitude or duration, failure of the bone tissue may result. Until recently the structural analysis of these fractures has been limited to two-dimensional sections. Due to the inherent destructiveness of this method, dynamic assessment of fracture progression has not been possible. An image-guided technique to analyze structural failure has been developed utilizing step-wise micro-compression in combination with time-lapsed micro-computed tomographic imaging. This technique allows, for the first time, direct three-dimensional visualization and quantification of fracture initiation and progression on the microscopic level and relates the global failure properties of trabecular bone to those of the individual trabeculae. The goals of this project were first to design and fabricate a novel micro-mechanical testing system, composed of a micro-compression device and a material testing and data acquisition system; and second, to validate the testing system to perform step-wise testing of trabecular bone specimens based on image-guided failure analysis. Due to the rate dependant properties of bone, stress relaxation was a concerning factor with respect to the step-wise testing method. In order to address these concerns, the results of the step-wise testing method were compared to those obtained from a conventional continuous test (considered to be the gold standard for the step-wise compressive mechanical testing) over the same total strain range and testing conditions. This was performed using porous aluminum alloy samples with highly reproducible and homogenous structural properties as well as trabecular bone samples from a single whale vertebra. Five cylinders from aluminum foam and trabecular whale bone each were compressed and imaged in a step-wise fashion from 0% to 20% strain at intervals of 2%, 4%, 8%, 12%, 16% and 20%. Mechanical properties obtained from the continuous and step-wise methods were not significantly different for both aluminum foam and whale bone specimens (p>0.05). Both testing methods yielded very similar stress-strain graphs with almost identical elastic and plastic regions with overlaying standard error bars for both whale bone and aluminum foam specimens. This was further concurred by performing regression analyses between the stress data from both testing methods (r(2)=0.98 for whale bone and aluminum foam specimens). Animations of fracture initiation and progression revealed that failure always occurred in local bands with the remaining regions of the structure largely unaffected independent of structure type. In conclusion, we found step-wise micro-compression to be a valid approach for image-guided failure assessment (IGFA) with high precision and accuracy as compared to classical continuous testing. We expect findings from upcoming studies of IGFA of human vertebral bone to improve our understanding of the relative importance of densitometric, morphological, and loading factors in the etiology of spontaneous fractures of the spine. Eventually, this improved understanding may lead to more successful approaches to the prevention of age-related fatigue fractures.

Animals↗
PubMed2004

Bone healing in the rat and dog with nonglycosylated BMP-2 demonstrating low solubility in fibrin matrices.

A novel form of recombinant human bone morphogenetic protein-2 (BMP-2) was explored for effective incorporation and long-term retention into fibrin ingrowth matrices. The solubility of native BMP-2 is greatly dependent on its glycosylation. To enhance retention of BMP-2 in fibrin matrices, a nonglycosylated form (nglBMP-2), which is less soluble than the native glycosylated protein, was produced recombinantly and evaluated in critical-size defects in the rat calvarium (group n=6). When 1 or 20 microg nglBMP-2 was incorporated by precipitation within the matrix, 74 +/- 4% and 98 +/- 2% healing was observed in the rat calvarium, respectively, as judged radiographically by closure of the defect at 3 weeks. More soluble forms of BMP-2, used as controls, induced less healing, demonstrating a positive correlation between low solubility, retention in vitro, and healing in vivo. Subsequently, the utility of nglBMP-2 was explored in a prospective veterinary clinical trial for inter-carpal fusion in dogs, replacing the standard-of-care, namely autologous cancellous autograft, with nglBMP-2 in fibrin. In a study of 10 sequential canine patients, fibrin with 600 microg/ml nglBMP-2 performed better than autograft in the first weeks of bone healing and comparably thereafter. Furthermore, a greater fraction of animals treated with nglBMP-2 in fibrin demonstrated bone bridging across each of the treated joints at both 12 and 17 weeks than in animals treated with autograft. These results suggest that evaluation in a human clinical setting of nonglycosylated BMP-2 in fibrin matrices might be fruitful.

Animals↗
PubMed2004

A finite element beam-model for efficient simulation of large-scale porous structures.

This paper presents a new method for the generation of a beam finite element (FE) model from a three-dimensional (3D) data set acquired by micro-computed tomography (micro-CT). This method differs from classical modeling of trabecular bone because it models a specific sample only and differs from conventional solid hexahedron element-based FE approaches in its computational efficiency. The stress-strain curve, characterizing global mechanical properties of a porous structure, could be well predicted (R(2)=0.92). Furthermore, validation of the method was achieved by comparing local displacements of element nodes with the displacements directly measured by time-lapsed imaging methods of failure, and these measures were in good agreement. The presented model is a first step in modeling specific samples for efficient strength analysis by FE modeling. We believe that with upcoming high-resolution in-vivo imaging methods, this approach could lead to a novel and accurate tool in the risk assessment for osteoporotic fractures.

Alloys↗
PubMed2003

Mapping quantitative trait loci for vertebral trabecular bone volume fraction and microarchitecture in mice.

UNLABELLED: BMD, which reflects both cortical and cancellous bone, has been shown to be highly heritable; however, little is known about the specific genetic factors regulating trabecular bone. Genome-wide linkage analysis of vertebral trabecular bone traits in 914 adult female mice from the F2 intercross of C57BL/6J and C3H/HeJ inbred strains revealed a pattern of genetic regulation derived from 13 autosomes, with 5-13 QTLs associated with each of the traits. Ultimately, identification of genes that regulate trabecular bone traits may yield important information regarding mechanisms that regulate mechanical integrity of the skeleton. INTRODUCTION: Both cortical and cancellous bone influence the mechanical integrity of the skeleton, with the relative contribution of each varying with skeletal site. Whereas areal BMD, which reflects both cortical and cancellous bone, has been shown to be highly heritable, little is known about the genetic determinants of trabecular bone density and architecture. MATERIALS AND METHODS: To identify heritable determinants of vertebral trabecular bone traits, we evaluated the fifth lumbar vertebra from 914 adult female mice from the F2 intercross of C57BL/6J (B6) and C3H/HeJ (C3H) progenitor strains. High-resolution microCT was used to assess total volume (TV), bone volume (BV), bone volume fraction (BV/TV), trabecular thickness (Tb.Th), separation (Tb.Sp), and number (Tb.N) of the trabecular bone in the vertebral body in the progenitors (n = 8/strain) and female B6C3H-F2 progeny (n = 914). Genomic DNA from F2 progeny was screened for 118 PCR-based markers discriminating B6 and C3H alleles on all 19 autosomes. RESULTS AND CONCLUSIONS: Despite having a slightly larger trabecular bone compartment, C3H progenitors had dramatically lower vertebral trabecular BV/TV (-53%) and Tb.N (-40%) and higher Tb.Sp (71%) compared with B6 progenitors (p < 0.001 for all). Genome-wide quantitative trait analysis revealed a pattern of genetic regulation derived from 13 autosomes, with 5-13 quantitative trait loci (QTLs) associated with each of the vertebral trabecular bone traits, exhibiting adjusted LOD scores ranging from 3.1 to 14.4. The variance explained in the F2 population by each of the individual QTL after adjusting for contributions from other QTLs ranged from 0.8% to 5.9%. Taken together, the QTLs explained 22-33% of the variance of the vertebral traits in the F2 population. In conclusion, we observed a complex pattern of genetic regulation for vertebral trabecular bone volume fraction and microarchitecture using the F2 intercross of the C57BL/6J and C3H/HeJ inbred mouse strains and identified a number of QTLs, some of which are distinct from those that were previously identified for total femoral and vertebral BMD. Identification of genes that regulate trabecular bone traits may ultimately yield important information regarding the mechanisms that regulate the acquisition and maintenance of mechanical integrity of the skeleton.

Animals↗
PubMed2003

Changes in bone architecture during spinal fusion: three years follow-up and the role of cage stiffness.

STUDY DESIGN: A morphometrical analysis of microcomputed tomography-based reconstructions of bone from the fusion zone in spinal cages. OBJECTIVE: To describe the architectural changes of the fusing bone tissue in time and to study the effect of cage stiffness on the development of the bone architecture within the cage. SUMMARY OF BACKGROUND DATA: Interbody fusion within spinal cages is routinely evaluated as either successful or not successful. The quality of the fusion, however, strongly depends on the architecture (i.e., structure and density) of the bone tissue within the cage. Bone architecture obviously changes during the fusion process, and cage stiffness is known to play a pivotal role. METHODS: Nine bone samples were available from a long-term in vivo study on resorbable spinal cages in Dutch milk goats described elsewhere. Follow-up periods of 3, 6, 12, 24, 30, and 36 months were considered for cages made of titanium or Poly L-Lactic Acid. The specimens were scanned with a resolution of 13 microm in a microcomputed tomography system. From the resulting reconstructions, the bone density; trabecular thickness, spacing, and number; connectivity density; and structure model index were assessed. RESULTS: We found a homogenization of all bone structure indexes along the spinal axis with time, and remarkably faster in the Poly L-Lactic Acid cages than in the titanium cages. After longer follow-up periods, a coarser bone structure with larger trabecular thickness and intertrabecular spacing was found. The structure model index appeared to be sensitive for nonunions. CONCLUSIONS: More "mature" spinal fusions showed a coarser and more homogeneous bone structure. High cage stiffness had a deteriorating effect on the fusion rate. The structure model index appears to be an interesting parameter for quantifying the quality of bone in the fusion zone.

Animals↗
PubMed2003

Does simvastatin stimulate bone formation in vivo?

BACKGROUND: Statins, potent compounds that inhibit cholesterol synthesis in the liver have been reported to induce bone formation, both in tissue culture and in rats and mice. To re-examine potential anabolic effects of statins on bone formation, we compared the activity of simvastatin (SVS) to the known anabolic effects of PTH in an established model of ovariectomized (OVX) Swiss-Webster mice. METHODS: Mice were ovariectomized at 12 weeks of age (T0), remained untreated for 5 weeks to allow development of osteopenia (T5), followed by treatment for 8 weeks (T13). Whole, trabecular and cortical femoral bone was analyzed by micro-computed tomography (micro CT). Liquid chromatography/mass spectrometry (LC/MS) was used to detect the presence of SVS and its active metabolite, simvastatin beta-hydroxy acid (SVS-OH) in the mouse serum. RESULTS: Trabecular BV/TV at T13 was 4.2 fold higher in animals treated with PTH (80 micro-g/kg/day) compared to the OVX-vehicle treated group (p < 0.001). However, the same comparison for the SVS-treated group (10 mg/kg/day administered by gavage) showed no significant difference (p = NS). LC/MS detected SVS and SVS-OH in mouse serum 20 minutes after gavage of 100 mg SVS. A serum osteocalcin assay (OC) demonstrated that neither bone formation nor osteoblast activity is significantly enhanced by SVS treatment in this in vivo study. CONCLUSIONS: While PTH demonstrated the expected anabolic effect on bone, SVS failed to stimulate bone formation, despite our verification by LC/MS of the active SVS-OH metabolite in mouse serum. While statins have clear effects on bone formation in vitro, the formulation of existing 'liver-targeted' statins requires further refinement for efficacy in vivo.

Animals↗
PubMed2003

Repair of bone defects using synthetic mimetics of collagenous extracellular matrices.

We have engineered synthetic poly(ethylene glycol) (PEG)-based hydrogels as cell-ingrowth matrices for in situ bone regeneration. These networks contain a combination of pendant oligopeptide ligands for cell adhesion (RGDSP) and substrates for matrix metalloproteinase (MMP) as linkers between PEG chains. Primary human fibroblasts were shown to migrate within these matrices by integrin- and MMP-dependent mechanisms. Gels used to deliver recombinant human bone morphogenetic protein-2 (rhBMP-2) to the site of critical- sized defects in rat crania were completely infiltrated by cells and were remodeled into bony tissue within five weeks. Bone regeneration was dependent on the proteolytic sensitivity of the matrices and their architecture. The cell-mediated proteolytic invasiveness of the gels and entrapment of rhBMP-2 resulted in efficient and highly localized bone regeneration.

Animals↗