Publications by authors named "Vincent A Stadelmann"

26 Publications

  • Page 1 of 1

The trochanteric double contour is a valuable landmark for assessing femoral offset underestimation on standard radiographs: a retrospective study.

BMC Musculoskelet Disord 2021 Mar 29;22(1):310. Epub 2021 Mar 29.

Department of Hip and Knee Surgery, Schulthess Klinik, Zürich, Switzerland.

Background: Inaccurate projection on standard pelvic radiographs leads to the underestimation of femoral offset-a critical determinant of postoperative hip function-during total hip arthroplasty (THA) templating. We noted that the posteromedial facet of the greater trochanter and piriformis fossa form a double contour on radiographs, which may be valuable in determining the risk of underestimating femoral offset. We evaluate whether projection errors can be predicted based on the double contour width.

Methods: Plain anteroposterior (AP) pelvic radiographs and magnetic resonance images (MRIs) of 64 adult hips were evaluated retrospectively. Apparent femoral offset, apparent femoral head diameter and double contour widths were evaluated from the radiographs. X-ray projection errors were estimated by comparison to the true neck length measured on MRIs after calibration to the femoral heads. Multivariate analysis with backward elimination was used to detect associations between the double contour width and radiographic projection errors. Femoral offset underestimation below 10% was considered acceptable for templating.

Results: The narrowest width of the double line between the femoral neck and piriformis fossa is significantly associated with projection error. When double line widths exceed 5 mm, the risk of projection error greater than 10% is significantly increased compared to narrower double lines, and the acceptability rate for templating drops below 80% (p = 0.02).

Conclusion: The double contour width is a potential landmark for excluding pelvic AP radiographs unsuitable for THA templating due to inaccurate femoral rotation.
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http://dx.doi.org/10.1186/s12891-021-04133-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008568PMC
March 2021

Impact of low bone mass and antiresorptive therapy on antibiotic efficacy in a rat model of orthopedic device-related infection.

J Orthop Res 2021 02 23;39(2):415-425. Epub 2020 Dec 23.

AO Research Institute Davos, Davos, Switzerland.

A significant proportion of orthopedic devices are implanted in osteoporotic patients, but it is currently unclear how estrogen deficiency and/or exposure to antiresorptive bisphosphonates (BPs) influence orthopedic device-related infection (ODRI), or response to therapy. The aim of this study is to characterize the bone changes resulting from Staphylococcus epidermidis infection in a rodent ODRI model and to determine if ovariectomy (OVX) or BP treatment influences the infection or the success of antibiotic therapy. A sterile or S. epidermidis-contaminated screw was implanted into the proximal tibia of skeletally mature female Wistar rats (n = 6-9 per group). Bone changes were monitored over 28 days using in vivo micro-computed tomography scanning. OVX was performed 12 weeks before screw implantation. The BP zoledronic acid (ZOL) was administered 4 days before screw insertion. A combination antibiotic regimen (rifampin plus cefazolin) was administered from Days 7-21. In skeletally healthy animals, S. epidermidis induced marked changes in bone, with peak osteolysis occurring at Day 9 and woven bone deposition and periosteal mineralization from Day 14 onwards. Antibiotic therapy cleared the infection in the majority of animals (2/9 infected) but did not affect bone responses. OVX did not affect the pattern of infection-induced changes in bone, nor bacterial load, but reduced antibiotic efficacy (5/9 infected). ZOL treatment did not protect from osteolysis in OVX animals, or further affect antibiotic efficacy (5/9 infected) but did significantly increase the bacterial load. This study suggests that both BPs and OVX can influence host responses to bone infections involving S. epidermidis.
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http://dx.doi.org/10.1002/jor.24951DOI Listing
February 2021

The impact of surgical strategy and rifampin on treatment outcome in Cutibacterium periprosthetic joint infections.

Clin Infect Dis 2020 Dec 10. Epub 2020 Dec 10.

Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, the Netherlands.

Background: Cutibacterium species are common pathogens in periprosthetic joint infections (PJI). These infections are often treated with β-lactams or clindamycin as monotherapy, or in combination with rifampin. Clinical evidence supporting the value of adding rifampin for treatment of Cutibacterium PJI is lacking.

Materials/methods: In this multicenter retrospective study, we evaluated patients with Cutibacterium PJI. The primary endpoint was clinical success, defined by the absence of infection relapse or new infection within a minimal follow-up of 12 months. We used Fisher's exact tests and Cox proportional hazards models to analyze the effect of rifampin and other factors on clinical success after PJI.

Results: We included 187 patients (72.2% male, median age 67 years) with a median follow-up of 36 months. The surgical intervention was two-stage exchange in 95 (50.8%), one-stage exchange in 51 (27.3%), debridement and implant retention (DAIR) in 34 (18.2%), and explantation without reimplantation in 7 (3.7%). Rifampin was included in the antibiotic regimen in 81 (43.3%) cases. Infection relapse occurred in 28 (15.0%), and new infection in 13 (7.0%) cases. In the time-to-event analysis, DAIR (adjusted HR=2.15, p=0.03) and antibiotic treatment over 6 weeks (adjusted HR=0.29, p=0.0002) significantly influenced treatment failure. We observed a tentative evidence for a beneficial effect of adding rifampin to the antibiotic treatment - though not statistically significant for treatment failure (adjusted HR=0.5, p=0.07) and not for relapses (adjusted HR=0.5, p=0.10).

Conclusions: We conclude that a rifampin combination is not markedly superior in Cutibacterium PJI but a dedicated prospective multicenter study is needed.
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http://dx.doi.org/10.1093/cid/ciaa1839DOI Listing
December 2020

Variable fixation promotes callus formation: an experimental study on transverse tibial osteotomies stabilized with locking plates.

BMC Musculoskelet Disord 2020 Dec 3;21(1):806. Epub 2020 Dec 3.

Musculoskeletal Research Unit (MSRU), Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.

Background: A new locking screw technology, named variable fixation, has been developed aiming at promoting bone callus formation providing initial rigid fixation followed by progressive fracture gap dynamisation. In this study, we compared bone callus formation in osteotomies stabilized with standard locking fixation against that of osteotomies stabilized with variable fixation in an established tibia ovine model.

Methods: A 3 mm tibial transverse osteotomy gap was stabilized in three groups of six female sheep each with a locking plate and either 1) standard fixation in both segments (group LS) or 2) variable fixation in the proximal and standard fixation in the distal bone segment (group VFLS) or 3) variable fixation in both segments (group VFLS). The implantation site and fracture healing were compared between groups by means of radiologic, micro tomographic, biomechanical, and histological investigations.

Results: Compared to LS callus, VFLS callus was 40% larger and about 3% denser, while VFLS callus was 93% larger and its density about 7.2% lower. VFLS showed 65% and VFLS 163% larger amount of callus at the cis-cortex. There wasn't a significant difference in the amount of callus at the cis and trans-cortex in groups featuring variable fixation only. Investigated biomechanical variables were not significantly different among groups and histology showed comparable good healing in all groups. Tissues adjacent to the implants did not show any alteration of the normal structure in all groups.

Conclusions: Variable fixation promoted the formation of a larger amount of bone callus, equally distributed at the cis and trans cortices. The histological and biomechanical properties of the variable fixation callus were equivalent to those of the standard fixation callus. The magnitude of variable fixation had a biological effect on the formation of bone callus. At the implantation site, the usage of variable fixation did not raise additional concerns with respect to standard fixation. The formation of a larger amount of mature callus suggests that fractures treated with variable fixation might have a higher probability to bridge the fracture gap. The conditions where its usage can be most beneficial for patients needs to be clinically defined.
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http://dx.doi.org/10.1186/s12891-020-03781-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713143PMC
December 2020

Longitudinal time-lapse in vivo micro-CT reveals differential patterns of peri-implant bone changes after subclinical bacterial infection in a rat model.

Sci Rep 2020 12 1;10(1):20901. Epub 2020 Dec 1.

AO Research Institute Davos, Clavadelerstrasse 8, 7270, Davos Platz, Switzerland.

Subclinical infection associated with orthopedic devices can be challenging to diagnose. The goal of this study was to evaluate longitudinal, microcomputed tomography (microCT) imaging in a rat model of subclinical orthopedic device-related infection caused by Staphylococcus epidermidis and four different Cutibacterium (previously Propionibacterium) acnes strains, and compare outcomes with non-inoculated and historical S. aureus-inoculated controls. Sterile screws or screws colonized with bacteria were placed in the tibia of 38 adult Wistar rats [n = 6 sterile screws; n = 6 S. epidermidis-colonized screws; n = 26 C. acnes-colonized screws (covering all three main subspecies)]. Regular microCT scans were taken over 28 days and processed for quantitative time-lapse imaging with dynamic histomorphometry. At euthanasia, tissues were processed for semiquantitative histopathology or quantitative bacteriology. All rats receiving sterile screws were culture-negative at euthanasia and displayed progressive bony encapsulation of the screw. All rats inoculated with S. epidermidis-colonized screws were culture-positive and displayed minor changes in peri-implant bone, characteristic of subclinical infection. Five of the 17 rats in the C. acnes inoculated group were culture positive at euthanasia and displayed bone changes at the interface of the screw and bone, but not deeper in the peri-implant bone. Dynamic histomorphometry revealed significant differences in osseointegration, bone remodeling and periosteal reactions between groups that were not measurable by visual observation of still microCT images. Our study illustrates the added value of merging 3D microCT data from subsequent timepoints and producing inherently richer 4D data for the detection and characterization of subclinical orthopedic infections, whilst also reducing animal use.
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http://dx.doi.org/10.1038/s41598-020-77770-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708479PMC
December 2020

The Impact of Heterotopic Ossification on Self-Reported Outcomes After Total Hip Arthroplasty Using the Direct Anterior Approach.

J Bone Joint Surg Am 2020 Nov;102(Suppl 2):91-98

Department of Hip and Knee Surgery, Schulthess Clinic, Zürich, Switzerland.

Background: Heterotopic ossification (HO) is a known finding after total hip arthroplasty (THA) that potentially affects clinical outcomes. The incidence of HO is related to various factors, including soft-tissue trauma, postoperative medication, surgical approach, and the surgeon's experience. Because use of the direct anterior approach (DAA) is gaining popularity, we aimed (1) to determine the incidence of HO after DAA-THA and (2) to evaluate the impact of HO on patient-reported outcomes (PROs).

Methods: We retrospectively reviewed 401 THAs (67 ± 10 years old, 210 men). The incidence and grade of HO were evaluated using the Brooker classification with anteroposterior and lateral radiographs. PROs were collected with use of the Oxford Hip Score (OHS) and the Core Outcome Measures Index (COMI)-Hip and were correlated with HO grades using generalized multiple regression models.

Results: The incidence of HO was 29.9% on the anteroposterior radiographic views (Brooker grade 1, 14.5%; grade 2, 11.1%; grade 3, 2.7%; and grade 4, 0.57%); the lateral radiographic views detected 9% additional HO when compared with the anteroposterior radiographs alone (Brooker grade 1, 8%, and grade 2, 1%). HO was more frequent in men. The American Society of Anesthesiologists (ASA) grade, age in women, and higher body mass index (BMI) in men were associated with higher HO grades. A transverse "bikini" incision was associated with a lower rate (4%) of Brooker grades 3 and 4 HO when compared with a longitudinal incision (12%). A Brooker grade of 0 to 3 HO did not impact outcomes. Only Brooker grade-4 HO was associated with significantly worse PROs; however, pain was not affected.

Conclusions: Low-grade HO after DAA-THA is not uncommon, and its rate is underestimated when anteroposterior radiographic views are evaluated without lateral views. The risk factors for developing HO in our cohort were an ASA grade of >3, male sex (especially with a high BMI), older age in women, and use of longitudinal incisions. With use of the bikini incision, patients had lower rates of severe HO, but mostly senior surgeons with more experience performed their surgery. Age, ASA grade, experience level of the surgeon, and Brooker grade-4 HO all had a significant influence on PROs. Clinically important HO (Brooker grade 4) remains rare after DAA-THR.

Level Of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.2106/JBJS.20.00071DOI Listing
November 2020

Orbital floor repair using patient specific osteoinductive implant made by stereolithography.

Biomaterials 2020 03 23;233:119721. Epub 2019 Dec 23.

AO Research Institute Davos, Clavadelerstrasse 8, CH 7270, Davos, Switzerland. Electronic address:

The orbital floor (OF) is an anatomical location in the craniomaxillofacial (CMF) region known to be highly variable in shape and size. When fractured, implants commonly consisting of titanium meshes are customized by plying and crude hand-shaping. Nevertheless, more precise customized synthetic grafts are needed to meticulously reconstruct the patients' OF anatomy with better fidelity. As alternative to titanium mesh implants dedicated to OF repair, we propose a flexible patient-specific implant (PSI) made by stereolithography (SLA), offering a high degree of control over its geometry and architecture. The PSI is made of biodegradable poly(trimethylene carbonate) (PTMC) loaded with 40 wt % of hydroxyapatite (called Osteo-PTMC). In this work, we developed a complete work-flow for the additive manufacturing of PSIs to be used to repair the fractured OF, which is clinically relevant for individualized medicine. This work-flow consists of (i) the surgical planning, (ii) the design of virtual PSIs and (iii) their fabrication by SLA, (iv) the monitoring and (v) the biological evaluation in a preclinical large-animal model. We have found that once implanted, titanium meshes resulted in fibrous tissue encapsulation, whereas Osteo-PMTC resulted in rapid neovascularization and bone morphogenesis, both ectopically and in the OF region, and without the need of additional biotherapeutics such as bone morphogenic proteins. Our study supports the hypothesis that the composite osteoinductive Osteo-PTMC brings advantages compared to standard titanium mesh, by stimulating bone neoformation in the OF defects. PSIs made of Osteo-PTMC represent a significant advancement for patients whereby the anatomical characteristics of the OF defect restrict the utilization of traditional hand-shaped titanium mesh.
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http://dx.doi.org/10.1016/j.biomaterials.2019.119721DOI Listing
March 2020

Relative effects of age on implant integration in a rat model: A longitudinal in vivo microct study.

J Orthop Res 2019 03 12;37(3):541-552. Epub 2019 Feb 12.

AO Research Institute Davos, Davos, Switzerland.

The effect of age on implant fixation in bone is not always considered during the design of preclinical models. The decision on animal's age is often related to practical or historical reasons, which ultimately may affect the reproducibility of results. This study aimed to quantify the effect of age by monitoring the fixation of contrast-enhanced PEEK screws in rats, hypothesizing that the kinetics of fixation is impaired in older animals but that age effects are less severe than osteoporotic effects. The time course of implant fixation was investigated in healthy rats at 24, 40, and 60 weeks of age; and in ovariectomized rats. Implant fixation was monitored using in-vivo microCT and dynamic histomorphometry during 1 month. The rats were euthanized 28 days post screw insertion. The data was analyzed both in absolute value and after normalization to baseline bone mass. In absolute terms, greater age had a detrimental effect on bone implant contact, bone fraction, implant stiffness, and bone remodeling but less than ovariectomy. Interestingly, once data was normalized to baseline bone mass this effect disappeared, suggesting that the physiologic response to implant placement was not affected by age. In conclusion, implant fixation kinetics is less affected by age than by baseline bone mass in this rat model. Animals of different ages can therefore be compared but data must be construed relatively to baseline bone mass and not in absolute terms. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:1-12, 2018.
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http://dx.doi.org/10.1002/jor.24210DOI Listing
March 2019

Spatially matching morphometric assessment of cartilage and subchondral bone in osteoarthritic human knee joint with micro-computed tomography.

Bone 2019 03 8;120:393-402. Epub 2018 Dec 8.

SCANCO Medical AG, Brüttisellen, Switzerland; Department of Research and Development, Schulthess Klinik, Zürich, Switzerland. Electronic address:

Objective: The objective of this study was to develop a reproducible and semi-automatic method based on micro computed tomography (microCT) to analyze cartilage and bone morphology of human osteoarthritic knee joints in spatially matching regions of interest.

Materials And Methods: Tibial plateaus from randomly selected patients with advanced osteoarthritis (OA) who underwent total knee arthroplasty surgery were microCT scanned once fresh and once after staining with Hexabrix. The articular surface was determined manually in the first scan. Total articular surface, defect surface and cartilage surface were computed by triangulation of the cartilage surface and the spatially corresponding subchondral bone regions were automatically generated and the standard cortical bone and trabecular bone morphometric indices were computed.

Results: The method to identify cartilage surface and defects was successfully validated against photographic examinations. The microCT measurements of the cartilage defect were also verified by conventional histopathology using safranin O-stained sections. Cartilage thickness and volume was significantly lower for OA condyle compared with healthy condyle. Bone fraction, bone tissue mineral density, cortical density and trabecular thickness differed significantly depending on the level of cartilage damage.

Conclusion: This new microCT imaging workflow can be used for reproducible quantitative evaluation of articular cartilage damage and the associated changes in subchondral bone morphology in osteoarthritic joints with a relatively high throughput compared to manual contouring. This methodology can be applied to gain better understanding of the OA disease progress in large cohorts.
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http://dx.doi.org/10.1016/j.bone.2018.12.003DOI Listing
March 2019

Five Days Granulocyte Colony-Stimulating Factor Treatment Increases Bone Formation and Reduces Gap Size of a Rat Segmental Bone Defect: A Pilot Study.

Front Bioeng Biotechnol 2018 12;6. Epub 2018 Feb 12.

AO Research Institute Davos, Davos, Switzerland.

Bone is an organ with high natural regenerative capacity and most fractures heal spontaneously when appropriate fracture fixation is provided. However, additional treatment is required for patients with large segmental defects exceeding the endogenous healing potential and for patients suffering from fracture non-unions. These cases are often associated with insufficient vascularization. Transplantation of CD34+ endothelial progenitor cells (EPCs) has been successfully applied to promote neovascularization of bone defects, however including extensive manipulation of cells. Here, we hypothesized, that treatment with granulocyte colony-stimulating factor (G-CSF) may improve bone healing by mobilization of CD34+ progenitor cells into the circulation, which in turn may facilitate vascularization at the defect site. In this pilot study, we aimed to characterize the different cell populations mobilized by G-CSF and investigate the influence of cell mobilization on the healing of a critical size femoral defect in rats. Cell mobilization was investigated by flow cytometry at different time points after five consecutive daily G-CSF injections. In a pilot study, bone healing of a 4.5-mm critical femoral defect in F344 rats was compared between a saline-treated control group and a G-CSF treatment group. microcomputed tomography and histology were applied to compare bone formation in both treatment groups. Our data revealed that leukocyte counts show a peak increase at the first day after the last G-CSF injection. In addition, we found that CD34+ progenitor cells, including EPCs, were significantly enriched at day 1, and further increased at day 5 and day 11. Upregulation of monocytes, granulocytes and macrophages peaked at day 1. G-CSF treatment significantly increased bone volume and bone density in the defect, which was confirmed by histology. Our data show that different cell populations are mobilized by G-CSF treatment in cell specific patterns. Although in this pilot study no bridging of the critical defect was observed, significantly improved bone formation by G-CSF treatment was clearly shown.
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http://dx.doi.org/10.3389/fbioe.2018.00005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816045PMC
February 2018

Fatigue as the missing link between bone fragility and fracture.

Nat Biomed Eng 2018 02 22;2(2):62-71. Epub 2018 Jan 22.

Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.

The prevention of fragility fractures in bone-pathologic fractures resulting from daily activity and mostly occurring in the elderly population-has been a long-term clinical quest. Recent research indicating that falls in the elderly might be the consequence of fracture rather than its cause has raised fundamental questions about the origin of fragility fractures. Is day-to-day cyclic loading, instead of a single-load event such as a fall, the main cause of progressively growing fractures? Are fragility fractures predominantly affected by bone quality rather than bone mass, which is the clinical indicator of fracture risk? Do osteocytes actively participate in the bone repair process? In this Perspective, we discuss the central role of cyclic fatigue in bone fragility fracture.
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http://dx.doi.org/10.1038/s41551-017-0183-9DOI Listing
February 2018

A doxycycline inducible, adenoviral bone morphogenetic protein-2 gene delivery system to bone.

J Tissue Eng Regen Med 2018 01 12;12(1):e106-e118. Epub 2017 Jun 12.

AO Research Institute Davos, Davos Platz, Switzerland.

We report the novel use of a tuneable, non-integrating viral gene delivery system to bone that can be combined with clinically approved biomaterials in an 'off-the-shelf' manner. Specifically, a doxycycline inducible Tet-on adenoviral vector (AdTetBMP-2) in combination with mesenchymal stromal cells (MSCs), fibrin and a biphasic calcium phosphate ceramic (MBCP®) was used to repair large bone defects in nude rats. Bone morphogenetic protein-2 (BMP-2) transgene expression could be effectively tuned by modification of the doxycycline concentration. The effect of adenoviral BMP-2 gene delivery upon bone healing was investigated in vivo in 4 mm critically sized, internally fixated, femoral defects. MSCs were transduced either by direct application of AdTetBMP-2 or by pre-coating MBCP granules with the virus. Radiological assessment scores post-mortem were significantly improved upon delivery of AdTetBMP-2. In AdTetBMP-2 groups, histological analysis revealed significantly more newly formed bone at the defect site compared with controls. Newly formed bone was vascularized and fully integrated with nascent tissue and implanted biomaterial. Improvement in healing outcome was achieved using both methods of vector delivery (direct application vs. pre-coating MCBP). Adenoviral delivery of BMP-2 enhanced bone regeneration achieved by the transplantation of MSCs, fibrin and MBCP in vivo. Importantly, our in vitro and in vivo data suggest that this can be achieved with relatively low (ng/ml) levels of the growth factor. Our model and novel gene delivery system may provide a powerful standardized tool for the optimization of growth factor delivery and release for the healing of large bone defects. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/term.2393DOI Listing
January 2018

Preclinical mouse models for assessing axial compression of long bones during exercise.

Bonekey Rep 2015 23;4:768. Epub 2015 Dec 23.

Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospitals & Faculty of Medicine , Geneva, Switzerland.

The aim of this laboratory method is to describe two approaches for the investigation of bone responses to mechanical loading in mice in vivo. The first is running exercise, because it is easily translatable clinically, and the second is axial compression of the tibia, because it is precisely controllable. The effects of running exercise, and in general physical activity, on bone tissue have been shown to be both direct through mechanical loading (ground impact and muscle tension) and indirect through metabolic changes. Therefore, running exercise has been considered the most convenient preclinical model for demonstrating the general idea that exercise is good for bone health, either early in age for increasing peak bone mass or later in age by slowing down bone loss. However, numerous combinations of protocols have been reported, which makes it difficult to formulate a simple take-home message. This laboratory method also provides a detailed description of in vivo direct mechanical axial compression of the mouse tibia. The effects of mechanical loading depend on the force (strain), frequency, waveform and duration of application, and they range from bone anabolism with low bone remodeling, inducing lamellar bone accumulation, to bone catabolism with high bone remodeling, leading to microdamage, woven bone formation and bone loss. Direct in vivo loading models are extensively used to study mechanotransduction pathways, and contribute by this way to the development of new bone anabolism treatments. Although it is particularly difficult to assemble an internationally adopted protocol description, which would give reproducible bone responses, here we have attempted to provide a comprehensive guide for best practice in performing running exercise and direct in vivo mechanical loading in the laboratory.
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http://dx.doi.org/10.1038/bonekey.2015.138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704463PMC
January 2016

Composite time-lapse computed tomography and micro finite element simulations: A new imaging approach for characterizing cement flows and mechanical benefits of vertebroplasty.

Med Eng Phys 2016 Feb 10;38(2):97-107. Epub 2015 Dec 10.

AO Research Institute Davos, Davos, Switzerland. Electronic address:

Vertebroplasty has been shown to reinforce weak vertebral bodies and reduce fracture risks, yet cement leakage is a major problem that can cause severe complications. Since cement flow is nearly impossible to control during surgery, small volumes of cement are injected, but then mechanical benefits might be limited. A better understanding of cement flows within bone structure is required to further optimize vertebroplasty and bone augmentation in general. We developed a novel imaging method, composite time-lapse CT, to characterize cement flow during injection. In brief, composite-resolution time-lapse CT exploits the qualities of microCT and clinical CT. The method consists in overlaying low-resolution time-lapse CT scans acquired during injection onto pre-operative high-resolution microCT scans, generating composite-resolution time-lapse CT series of cement flow within bone. In this in vitro study, composite-resolution time-lapse CT was applied to eight intact and five artificially fractured cadaveric vertebrae during vertebroplasty. The time-lapse scans were acquired at one-milliliter cement injection steps until a total of 10 ml cement was injected. The composite-resolution series were then converted into micro finite element models to compute strains distribution under virtual axial loading. Relocation of strain energy density within bone structure was observed throughout the progression of the procedure. Interestingly, the normalized effect of cement injection on the overall stiffness of the vertebrae was similar between intact and fractured specimens, although at different orders of magnitude. In conclusion, composite time-lapse CT can picture cement flows during bone augmentation. The composite images can also be easily converted into finite element models to compute virtual strain distributions under loading at every step of an injection, providing deeper understanding on the biomechanics of vertebroplasty.
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http://dx.doi.org/10.1016/j.medengphy.2015.10.007DOI Listing
February 2016

In Vivo MicroCT Monitoring of Osteomyelitis in a Rat Model.

Biomed Res Int 2015 29;2015:587857. Epub 2015 Apr 29.

AO Research Institute Davos, Clavadelerstrasse 8, 7270 Davos-Platz, Switzerland.

Infection associated with orthopedic implants often results in bone loss and requires surgical removal of the implant. The aim of this study was to evaluate morphological changes of bone adjacent to a bacteria-colonized implant, with the aim of identifying temporal patterns that are characteristic of infection. In an in vivo study with rats, bone changes were assessed using in vivo microCT at 7 time points during a one-month postoperative period. The rats received either a sterile or Staphylococcus aureus-colonized polyetheretherketone screw in the tibia. Bone-implant contact, bone fraction, and bone changes (quiescent, resorbed, and new bone) were calculated from consecutive scans and validated against histomorphometry. The screw pullout strength was estimated from FE models and the results were validated against mechanical testing. In the sterile group, bone-implant contact, bone fraction, and mechanical fixation increased steadily until day 14 and then plateaued. In the infected group, they decreased rapidly. Bone formation was reduced while resorption was increased, with maximum effects observed within 6 days. In summary, the model presented is capable of evaluating the patterns of bone changes due to implant-related infections. The combined use of longitudinal in vivo microCT imaging and image-based finite element analysis provides characteristic signs of infection within 6 days.
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http://dx.doi.org/10.1155/2015/587857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429214PMC
March 2016

A Nucleotomy Model with Intact Annulus Fibrosus to Test Intervertebral Disc Regeneration Strategies.

Tissue Eng Part C Methods 2015 Nov 8;21(11):1117-24. Epub 2015 Jul 8.

1 Department of Orthopedic and Trauma Surgery, Campus Bio-Medico University of Rome , Rome, Italy .

Introduction: New cells/hydrogel-based treatments for intervertebral disc (IVD) regeneration need to be tested on animal models before clinical translation. Ovine IVD represents a good model but does not allow the injection of a significant volume into intact IVD. The aim of this study was to compare different methods to create a cavity into ovine nucleus pulposus (NP) by enzymatic digestion (E), mechanical nucleotomy (N), or a combining technique (E+N), as a model to study IVD regeneration strategies with intact annulus fibrosus (AF) in functional spinal units (FSUs) in vitro.

Methods: The transpedicular approach via the endplate route (2 mm tunnel) was performed on ovine FSU (IVD and superior and inferior endplate) to access the NP. FSUs were treated by N (Arthroscopic shaver), E (Trypsin/Collagenase), or E+N. Treatments were evaluated macro- and microscopically. The degradation of proteoglycan (PG) around the cavity was assessed by gel electrophoresis. Cell viability was evaluated using the lactate dehydrogenase (LDH) assay. Cavity volume was quantified through computerized tomography after injection of agarose gel/contrast agent.

Results: A cavity with intact AF was successfully created with all three methods. The N group showed high reproducibility, low PG degradation, and no endplate thinning. Histological analysis demonstrated NP matrix degradation in enzyme-treated groups, while the PG content was homogenous using mechanical discectomy. Cell viability was affected only in the E group. The cavity volume normalized to the total IVD volume was 5.2% ± 1.6% in E, 5.0% ± 1.4% in E+N, and 4.2% ± 0.1% in N.

Conclusions: Mechanical nucleotomy leads to a more reproducible and less destructive cavity in the NP. Enzymatic methods perform better in terms of cavity volume; however, the cells and PG of the surrounding tissue may be affected. The mechanical nucleotomy enables the creation of a cavity into the IVD while keeping the AF intact, allowing the injection of reproducible volumes of hydrogel and tissue engineering construct for preclinical tests.
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http://dx.doi.org/10.1089/ten.TEC.2015.0086DOI Listing
November 2015

Multiphasic modelling of bone-cement injection into vertebral cancellous bone.

Int J Numer Method Biomed Eng 2015 Jan 27;31(1):e02696. Epub 2015 Jan 27.

Institute of Applied Mechanics (CE), University of Stuttgart, Pfaffenwaldring 7, 70569, Stuttgart, Germany; Stuttgart Research Centre for Simulation Technology, Pfaffenwaldring 5a, 70569, Stuttgart, Germany.

Percutaneous vertebroplasty represents a current procedure to effectively reinforce osteoporotic bone via the injection of bone cement. This contribution considers a continuum-mechanically based modelling approach and simulation techniques to predict the cement distributions within a vertebra during injection. To do so, experimental investigations, imaging data and image processing techniques are combined and exploited to extract necessary data from high-resolution μCT image data. The multiphasic model is based on the Theory of Porous Media, providing the theoretical basis to describe within one set of coupled equations the interaction of an elastically deformable solid skeleton, of liquid bone cement and the displacement of liquid bone marrow. The simulation results are validated against an experiment, in which bone cement was injected into a human vertebra under realistic conditions. The major advantage of this comprehensive modelling approach is the fact that one can not only predict the complex cement flow within an entire vertebra but is also capable of taking into account solid deformations in a fully coupled manner. The presented work is the first step towards the ultimate and future goal of extending this framework to a clinical tool allowing for pre-operative cement distribution predictions by means of numerical simulations.
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http://dx.doi.org/10.1002/cnm.2696DOI Listing
January 2015

Magnetic resonance imaging in zirconia-based dental implantology.

Clin Oral Implants Res 2015 Oct 4;26(10):1195-202. Epub 2014 Jun 4.

Department of Oral and Craniomaxillofacial Surgery, University Hospital Freiburg, Freiburg, Germany.

Objectives: X-ray-based planning and post-implantation assessment of titanium implants is the commonly accepted standard to date. However, new implant materials such as zirconia (ZrO2 ) have become available, and magnetic resonance imaging may be a valuable alternative with these implants. The present in vitro study investigated artifacts produced by titanium and zirconia implants in magnetic resonance imaging (MRI) and assessed the accuracy of pre-implant planning and post-implantation assessment comparing MRI to standard X-ray-based imaging modalities: Orthopantomogram (OPT), cone beam (CBCT), and computed tomography (CT).

Materials And Methods: Twelve porcine mandibles were prepared and scanned (MRI, OPT, CBCT, μCT), and bone height above the nerve canal was measured. Specimens were implanted with either two titanium or zirconia implants and rescanned to investigate the influence of implant materials on post-implantation assessment. MRI and μCT artifacts were quantified with implants embedded in gelatin phantoms and porcine specimens.

Results: Compared with CBCT set as standard, μCT, OPT, and MRI showed similar accuracy in pre-op bone height measurements. Post-implantation, while titanium implants induced a strong B0 -field distortion resulting in extensive signal voids, zirconia implants were clearly depictable with only minor distortions.

Conclusions: Excellent contrast, limited artifacts, radiation-free and accurate implant assessment may indicate that MRI is a valuable imaging alternative for zirconia-based implant dentistry.
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http://dx.doi.org/10.1111/clr.12430DOI Listing
October 2015

Microstructural parameters of bone evaluated using HR-pQCT correlate with the DXA-derived cortical index and the trabecular bone score in a cohort of randomly selected premenopausal women.

PLoS One 2014 13;9(2):e88946. Epub 2014 Feb 13.

AO Research Institute Davos, Davos, Switzerland.

Background: Areal bone mineral density is predictive for fracture risk. Microstructural bone parameters evaluated at the appendicular skeleton by high-resolution peripheral quantitative computed tomography (HR-pQCT) display differences between healthy patients and fracture patients. With the simple geometry of the cortex at the distal tibial diaphysis, a cortical index of the tibia combining material and mechanical properties correlated highly with bone strength ex vivo. The trabecular bone score derived from the scan of the lumbar spine by dual-energy X-ray absorptiometry (DXA) correlated ex vivo with the micro architectural parameters. It is unknown if these microstructural correlations could be made in healthy premenopausal women.

Methods: Randomly selected women between 20-40 years of age were examined by DXA and HR-pQCT at the standard regions of interest and at customized sub regions to focus on cortical and trabecular parameters of strength separately. For cortical strength, at the distal tibia the volumetric cortical index was calculated directly from HR-pQCT and the areal cortical index was derived from the DXA scan using a Canny threshold-based tool. For trabecular strength, the trabecular bone score was calculated based on the DXA scan of the lumbar spine and was compared with the corresponding parameters derived from the HR-pQCT measurements at radius and tibia.

Results: Seventy-two healthy women were included (average age 33.8 years, average BMI 23.2 kg/m(2)). The areal cortical index correlated highly with the volumetric cortical index at the distal tibia (R  =  0.798). The trabecular bone score correlated moderately with the microstructural parameters of the trabecular bone.

Conclusion: This study in randomly selected premenopausal women demonstrated that microstructural parameters of the bone evaluated by HR-pQCT correlated with the DXA derived parameters of skeletal regions containing predominantly cortical or cancellous bone. Whether these indexes are suitable for better predictions of the fracture risk deserves further investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088946PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923873PMC
October 2014

In vivo monitoring of bone-implant bond strength by microCT and finite element modelling.

Comput Methods Biomech Biomed Engin 2013 30;16(9):993-1001. Epub 2012 Jan 30.

a McCaig Institute for Bone and Joint Health, Human Performance Laboratory, Schulich School of Engineering, University of Calgary , Calgary , Canada.

Immediately after implantation, a dynamic process of bone formation and resorption takes place around an orthopaedic implant, influencing its mechanical fixation. The delay until complete fixation depends on local bone architecture and metabolism. Despite its importance, the temporal pattern of implant fixation is still unknown. The optimal duration of post-operative care is therefore difficult to establish for an individual situation, and a method to evaluate non-invasively the evolution of the mechanical stability would be a significant asset in a clinical environment. The aim of this study was to evaluate the potential of micro-finite element modelling based on in vivo micro-computed tomography to monitor longitudinally the contact between bone and implant and the implant strength in vivo. The model was first validated for screw pull-out in synthetic bone surrogate. Correlation coefficients of R(2) = 0.94 and 0.85 (p < 0.01) were measured between experimental and numerical results for stiffness and failure loads, respectively. Then, the mechanical integration of screws in the proximal tibia of 12 rats was monitored at seven time points over a period of 1 month. We observed significant increases (p < 0.05) of bone-screw contact (+28%), stiffness (+93%) and failure load (+71%) over the course of the experiment, and more than 75% of these changes occurred during the first 2 weeks. Limitations, such as image artefacts and radiation, still compromise the immediate clinical application of this method, but it has a promising potential in preclinical animal studies, as it provides very valuable data about the dynamic aspect of implant integration with considerably reduced animal resources.
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http://dx.doi.org/10.1080/10255842.2011.648625DOI Listing
May 2014

Calcium phosphate cement augmentation of cancellous bone screws can compensate for the absence of cortical fixation.

J Biomech 2010 Nov 21;43(15):2869-74. Epub 2010 Aug 21.

Laboratory of Biomechanical Orthopedics, Institute of Bioengineering, EPFL, EPFL/STI/IBI/LBO, Station 15, 1015 Lausanne, Switzerland.

An obvious means to improve the fixation of a cancellous bone screw is to augment the surrounding bone with cement. Previous studies have shown that bone augmentation with Calcium Phosphate (CaP) cement significantly improves screw fixation. Nevertheless, quantitative data about the optimal distribution of CaP cement is not available. The present study aims to show the effect of cement distribution on the screw fixation strength for various cortical thicknesses and to determine the conditions at which cement augmentation can compensate for the absence of cortical fixation in osteoporotic bone. In this study, artificial bone materials were used to mimic osteoporotic cancellous bone and cortical bone of varying thickness. These bone constructs were used to test the fixation strength of cancellous bone screws in different cortical thicknesses and different cement augmentation depths. The cement distribution was measured with microCT. The maximum pullout force was measured experimentally. The microCT analysis revealed a pseudo-conic shape distribution of the cement around the screws. While the maximum pullout strength of the screws in the artificial bone only was 30±7N, it could increase up to approximately 1000N under optimal conditions. Cement augmentation significantly increased pullout force in all cases. The effect of cortical thickness on pullout force was reduced with increased cement augmentation depth. Indeed, cement augmentation without cortical fixation increased pullout forces over that of screws without cement augmentation but with cortical fixation. Since cement augmentation significantly increased pullout force in all cases, we conclude that the loss of cortical fixation can be compensated by cement augmentation.
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http://dx.doi.org/10.1016/j.jbiomech.2010.07.025DOI Listing
November 2010

Prediction of bone density around orthopedic implants delivering bisphosphonate.

J Biomech 2009 Jun 19;42(9):1206-11. Epub 2009 Apr 19.

Laboratory of Biomechanical Orthopedics, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

The fixation of an orthopedic implant depends strongly upon its initial stability. Peri-implant bone may resorb shortly after the surgery. This resorption is directly followed by new bone formation and implants fixation strengthening, the so-called secondary fixation. If the initial stability is not reached, the resorption continues and the implant fixation weakens, which leads to implant loosening. Studies with rats and dogs have shown that a solution to prevent peri-implant resorption is to deliver bisphosphonate from the implant surface. The aims of the study were, first, to develop a model of bone remodeling around an implant delivering bisphosphonate, second, to predict the bisphosphonate dose that would induce the maximal peri-implant bone density, and third to verify in vivo that peri-implant bone density is maximal with the calculated dose. The model consists of a bone remodeling equation and a drug diffusion equation. The change in bone density is driven by a mechanical stimulus and a drug stimulus. The drug stimulus function and the other numerical parameters were identified from experimental data. The model predicted that a dose of 0.3 microg of zoledronate on the implant would induce a maximal bone density. Implants with 0.3 microg of zoledronate were then implanted in rat femurs for 3, 6 and 9 weeks. We measured that peri-implant bone density was 4% greater with the calculated dose compared to the dose empirically described as best. The approach presented in this paper could be used in the design and analysis processes of experiments in local delivery of drug such as bisphosphonate.
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http://dx.doi.org/10.1016/j.jbiomech.2009.03.024DOI Listing
June 2009

3D strain map of axially loaded mouse tibia: a numerical analysis validated by experimental measurements.

Comput Methods Biomech Biomed Engin 2009 Feb;12(1):95-100

Laboratory of Biomechanical Orthopedics EPFL-HOSR, Institute of Translational Biomechanics, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland.

A combined experimental/numerical study was performed to calculate the 3D octahedral shear strain map in a mouse tibia loaded axially. This study is motivated by the fact that the bone remodelling analysis, in this in vivo mouse model should be performed at the zone of highest mechanical stimulus to maximise the measured effects. Accordingly, it is proposed that quantification of bone remodelling should be performed at the tibial crest and at the distal diaphysis. The numerical model could also be used to furnish a more subtle analysis as a precise correlation between local strain and local biological response can be obtained with the experimentally validated numerical model.
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http://dx.doi.org/10.1080/10255840903077287DOI Listing
February 2009

Orthopedic implant used as drug delivery system: clinical situation and state of the research.

Curr Drug Deliv 2008 Jan;5(1):59-63

Laboratory of Biomechanical Orthopedics EPFL-HOSR, Institute of Translational Biomechanics, Ecole Polytechnique Fédérale Lausanne, Switzerland.

A partial review is proposed on the existing literature for the research performed in orthopedic implant used as drug delivery system. In the first part, an evaluation is given on the clinical need to deliver a drug in the surrounding of an implant. Secondly, a review of the clinical situation is developed for implants already used as drug delivery system. Experimental works performed for local delivery are reported. In particular, a description is given on the in vitro and in vivo studies where the implant is coated with different proteins or drugs. Finally, a conclusion is proposed on the next step in the development of orthopedic implant as drug delivery system mentioning also the industrial situation.
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http://dx.doi.org/10.2174/156720108783331041DOI Listing
January 2008

Microstimulation at the bone-implant interface upregulates osteoclast activation pathways.

Bone 2008 Feb 5;42(2):358-64. Epub 2007 Oct 5.

Laboratory of Biomechanical Orthopedics EPFL-HOSR, Institute of Translational Biomechanics, Station 15, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.

Peri-implant bone resorption after total joint arthroplasty is a key parameter in aseptic loosening. Implant wear debris and biomechanical aspects have both been demonstrated to be part of the bone resorption process. However, neither of these two parameters has been clearly identified as the primary initiator of peri-implant bone resorption. For the biomechanical parameters, micromotions were measured at the bone-implant interface during normal gait cycles. The amplitude of the micromotions was shown to trigger differentiation of bone tissues. So far no data exists directly quantifying the effect of micromotion and compression on human bone. We hypothesize that micromotion and compression at the bone-implant interface may induce direct activation of bone resorption around the implant through osteoblasts-osteoclasts cell signaling in human bone. This hypothesis was tested with an ex vivo loading system developed to stimulate trabecular bone cores and mimic the micromotions arising at the bone-implant interface. Gene expression of RANKL, OPG, TGFB2, IFNG and CSF-1 was analyzed after no mechanical stimulation (control), exposure to compression or exposure to micromotions. We observed an 8-fold upregulation of RANKL after exposure to micromotions, and downregulation of OPG, IFNG and TGFB2. The RANKL:OPG ratio was upregulated 24-fold after micromotions. This suggests that the micromotions arising at the bone-implant interface during normal gait cycles induce a bone resorption response after only 1 h, which occurs before any wear debris particles enter the system.
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http://dx.doi.org/10.1016/j.bone.2007.09.055DOI Listing
February 2008

Osteopenia, decreased bone formation and impaired osteoblast development in Sox4 heterozygous mice.

J Cell Sci 2007 Aug 24;120(Pt 16):2785-95. Epub 2007 Jul 24.

Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.

The transcription factor Sox4 is vital for fetal development, as Sox4(-/-) homozygotes die in utero. Sox4 mRNA is expressed in the early embryonic growth plate and is regulated by parathyroid hormone, but its function in bone modeling/remodeling is unknown. We report that Sox4(+/-) mice exhibit significantly lower bone mass (by dual-energy X-ray absorptiometry) from an early age, and fail to obtain the peak bone mass of wild-type (WT) animals. Microcomputed tomography (muCT), histomorphometry and biomechanical testing of Sox4(+/-) bones show reduced trabecular and cortical thickness, growth plate width, ultimate force and stiffness compared with WT. Bone formation rate (BFR) in 3-month-old Sox4(+/-) mice is 64% lower than in WT. Primary calvarial osteoblasts from Sox4(+/-) mice demonstrate markedly inhibited proliferation, differentiation and mineralization. In these cultures, osterix (Osx) and osteocalcin (OCN) mRNA expression was reduced, whereas Runx2 mRNA was unaffected. No functional defects were found in osteoclasts. Silencing of Sox4 by siRNA in WT osteoblasts replicated the defects observed in Sox4(+/-) cells. We demonstrate inhibited formation and altered microarchitecture of bone in Sox4(+/-) mice versus WT, without apparent defects in bone resorption. Our results implicate the transcription factor Sox4 in regulation of bone formation, by acting upstream of Osx and independent of Runx2.
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http://dx.doi.org/10.1242/jcs.003855DOI Listing
August 2007