Papers by Vincent Stadelmann
Clinical oral investigations, Jan 7, 2015
Bisphosphonate-related osteonecrosis of the jaw (BP-ONJ) occurs in 1 % of patients with medicatio... more Bisphosphonate-related osteonecrosis of the jaw (BP-ONJ) occurs in 1 % of patients with medication-induced osteoporosis treated with bisphosphonates. Sheep are an established large animal model for investigating osteoporotic skeletal changes. Zoledronate significantly reduces tissue mineral variability in ovariectomized sheep. The aim of this study was to analyze bone healing after tooth extraction in sheep with induced osteopenia and zoledronate administration. Eight adult ewes were randomly divided into two groups of four animals. All sheep underwent ovariectomy and a low-calcium diet. Dexamethasone was administered weekly for 16 weeks. Zoledronate was then given every third week for a further 16 weeks in four sheep; these infusions were repeated after extraction of two lower premolars. Four sheep without zoledronate administrations served as controls. Due to general health conditions, two sheep of the zoledronate group had to be excluded before surgery. The remaining two sheep of...
Medicine, 2015
Augmentation of implants with polymethylmethacrylate (PMMA) bone cement in osteoporotic fractures... more Augmentation of implants with polymethylmethacrylate (PMMA) bone cement in osteoporotic fractures is a promising approach to increase implant purchase. Side effects of PMMA for the metaphyseal bone, particularly for the adjacent subchondral bone plate and joint cartilage, have not yet been studied. The following experimental study investigates whether subchondral PMMA injection compromises the homeostasis of the subchondral bone and/or the joint cartilage.Ten mature sheep were used to simulate subchondral PMMA injection. Follow-ups of 2 (4 animals) and 4 (6 animals) months were chosen to investigate possible cartilage damage and subchondral plate alterations in the knee. Evaluation was completed by means of high-resolution peripheral quantitative computed tomography (HRpQCT) imaging, histopathological osteoarthritis scoring, and determination of glycosaminoglycan content in the joint cartilage. Results were compared with the untreated contralateral knee and statistically analyzed using nonparametric tests.Evaluation of the histological osteoarthritis score revealed no obvious cartilage damage for the treated knee; median histological score after 2 months 0 (range 4), after 4 months 1 (range 5). There was no significant difference when compared with the untreated control site after 2 and 4 months (P = 0.23 and 0.76, respectively). HRpQCT imaging showed no damage to the metaphyseal trabeculae. Glycosaminoglycan measurements of the treated joint cartilage after 4 months revealed no significant difference compared with the untreated cartilage (P = 0.24).The findings of this study support initial clinical observation that PMMA implant augmentation of metaphyseal fractures appears to be a safe procedure for fixation without harming the subchondral bone plate and adjacent joint cartilage.
PLoS ONE, 2014
Background: Areal bone mineral density is predictive for fracture risk. Microstructural bone para... more 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.
Frontiers in bioengineering and biotechnology, 2018
Bone is an organ with high natural regenerative capacity and most fractures heal spontaneously wh... more 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 critica...
Journal of Tissue Engineering and Regenerative Medicine, 2016
We report the novel use of a tuneable, non-integrating viral gene delivery system to bone that ca... more 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. BMP-2 transgene expression could be effectively tuned by modification of 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 to controls. Newly formed bone was vascularised 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 suggests 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 standardised tool for the optimisation of growth factor delivery and release for the healing of large bone defects. This article is protected by copyright. All rights reserved.
Journal of Biomechanics, Jun 19, 2009
The fixation of an orthopedic implant depends strongly upon its initial stability. Peri-implant b... more 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.
ABSTRACT local bisphosphonate delivery may be a solution to prevent periprosthetic bone loss and ... more ABSTRACT local bisphosphonate delivery may be a solution to prevent periprosthetic bone loss and improve orthopedic implants fixation. In load-bearing implants, periprosthetic bone is exposed to high mechanical demands, which in normal conditions induce an adaptation of bone. In this specific mechanical situation, the modulation of the bone response by bisphosphonate remains uncertain. we assessed the combined effects of zoledronate and mechanical loading on bone adaptation using an in-vivo axial compression model of the mouse tibia and injections of zoledronate. Bone structure was quantified with in-vivo microCT before and after the period of stimulation and the mechanical properties of the tibias were evaluated with 3 point-bending tests after sacrifice. axial loading induced a localized increase of cortical thickness and bone area. Zoledronate increased cortical thickness, bone perimeter, and bone area. At the most loaded site of the tibia, the combined effect of zoledronate and mechanical stimulation was significantly smaller than the sum of the individual effects measured at the same site in the control groups. the results of this study suggested that a negative interaction between zoledronate and mechanical loading might exist at high level of strain.
Dentomaxillofacial Radiology, 2016
Bisphosphonate-associated osteonecrosis of the jaw (BP-ONJ) is a side effect of antiresorptive tr... more Bisphosphonate-associated osteonecrosis of the jaw (BP-ONJ) is a side effect of antiresorptive treatment that is increasingly prescribed for patients with osteoporosis or malignant diseases with bone metastases. Surgical treatment of BP-ONJ requires adequate pre-operative imaging. To date, CT is the imaging standard in clinical routine; however, defining the extent of the pathological area is difficult and soft tissues are poorly displayed. MRI with zero echo time (ZTE-MRI) to display hard tissues enables a precise display of calcified structures and soft tissues for the delineation of bone necrosis and soft-tissue reactions. BP-ONJ was induced in eight sheep by extraction of two premolars in the left mandible and zoledronate (ZOL) administration. Eight sheep without ZOL administration served as the control group. Four sheep of each main group underwent osteopenia induction via ovariectomy, glucocorticoid administration and a calcium-free diet. After sacrifice, the area of tooth extraction was harvested and scanned with micro-CT (µCT) and ZTE-MRI. Two trained dentists analyzed digital imaging and communications in medicine data sets using three-dimensional imaging software. The periosteal reaction and the remaining extraction sockets were measured. BP-ONJ was evident, and the remaining extraction sockets were observed in all animals treated with ZOL. Periosteal reactions were more pronounced in animals treated with ZOL, and they appeared broader in ZTE-MRI. BP-ONJ lesions in the sheep mandible can be detected using µCT and ZTE-MRI. Although illustration of sequester was more consistent using the µCT, ZTE-MRI was advantageous in evaluation of periosteal reaction.
Bone, Feb 29, 2008
Peri-implant bone resorption after total joint arthroplasty is a key parameter in aseptic looseni... more 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 boneimplant 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.
BoneKEy Reports, 2015
The aim of this laboratory method is to describe two approaches for the investigation of bone res... more 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.
PAMM, 2013
ABSTRACT The reinforcement of porous vertebral cancellous bone by the injection of bone cement is... more ABSTRACT The reinforcement of porous vertebral cancellous bone by the injection of bone cement is a practical procedure for the stabilisation of osteoporotic compression fractures and other weakening lesions. This contribution concerns the reproduction and prediction of the resulting bone-cement distribution during the injection procedure by means of numerical simulation. A detailed micromechanical (locally single-phasic) model exhibits the drawback that all geometrical and physical transition conditions of the individual parts of the complex aggregate have to be known. Therefore, we rather proceed from a macroscopic (and multi-constituent) continuum-mechanical model based on the Theory of Porous Media. In this regard, the homogenisation of the underlying micro-structure results in a model of three constituents: these are the solid bone skeleton, which is saturated by the liquid bone marrow that may be displaced by the injected liquid bone cement. The influence of the micro-architecture of the pore space on the spreading of the bone cement is considered by a spatial diversification of the anisotropic permeability tensors, obtained through image processing techniques applied to medical imaging data (µCT). The numerical investigation of the strongly coupled problem enables the study of vertebroplasty and allows for the comparison between the simulation results and the experimentally determined bone-cement distribution that were imaged during injections. (© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)
PAMM, 2014
ABSTRACT The stability of the human spine is highly dependent on the cancellous bone structure of... more ABSTRACT The stability of the human spine is highly dependent on the cancellous bone structure of the vertebra. In the case of osteoporosis and accompanied weaking of the vertebral structure, compression fractures and other lesions of the affected patient may occur. The reinforcement of the porous cancellous bone by the injection of bone-cement is a common procedure in order to overcome this issues. The modelling and computational simulation of vertebroplasty, i.e., bone-cement-injection into the vertebra, is of major interest to obtain valid and reliable predicitions for this surgery. A detailed micromechanical (and locally single-phasic) model exhibits the drawback that all geometrical and physical transition conditions of the individual parts and their complex microstructure have to be known. Therefore, this study considers a macro-scopic (and multi-constituent) continuum-mechanical model based on the Theory of Porous Media, where the homogenisation of the underlying micro-structure results in a model of three constituents. In particular, these are the solid bone skeleton, which is saturated by bone marrow, where the latter may be displaced by the injected liquid bone cement. The micro-architecture is regarded by heterogeneous and anisotropic permeability tensors and the preferred directions of the trabecular bone structure. The presented strongly coupled macroscopic model offers the opportunity to not only simulate the flow of the pore fluids but also predicts the arising stresses and strains of the solid bone skeleton due to the numerical investigation of the injection process. (© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)
Tissue engineering. Part C, Methods, Jan 2, 2015
New cells/hydrogel based treatments for IVD regeneration need to be tested on animal models befor... more New cells/hydrogel based treatments for 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 intervertebral disc (IVD) regeneration strategies with intact annulus fibrosus (AF) in functional spinal units (FSU) in vitro. 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 micro-scopically. The degradation of proteoglycan (PG) around the cavity was assessed by gel electrophoresis. Cell viability was evaluated using the lactate dehyd...
ASME 2007 Summer Bioengineering Conference, 2007
ASME 2007 Summer Bioengineering Conference, 2007
Page 1. Copyright © 2007 by ASME 1 INTRODUCTION Bone turnover serves different purposes. It allow... more Page 1. Copyright © 2007 by ASME 1 INTRODUCTION Bone turnover serves different purposes. It allows the bone to adapt its shape to the actual constraints, it regulates the serum levels of calcium and other ions, and it repairs structural defects of bone. ...
International journal for numerical methods in biomedical engineering, 2015
Percutaneous vertebroplasty represents a current procedure to effectively reinforce osteoporotic ... more 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 pre...
European cells & materials, 2008
It is a clinical challenge to obtain a sufficient orthopaedic implant fixation in weak osteoporot... more It is a clinical challenge to obtain a sufficient orthopaedic implant fixation in weak osteoporotic bone. When the primary implant fixation is poor, micromotions occur at the bone-implant interface, activating osteoclasts, which leads to implant loosening. Bisphosphonate can be used to prevent the osteoclastic response, but when administered systemically its bioavailability is low and the time it takes for the drug to reach the periprosthetic bone may be a limiting factor. Recent data has shown that delivering bisphosphonate locally from the implant surface could be an interesting solution. Local bisphosphonate delivery increased periprosthetic bone density, which leads to a stronger implant fixation, as demonstrated in rats by the increased implant pullout force. The aim of the present study was to verify the positive effect on periprosthetic bone remodelling of local bisphosphonate delivery in an osteoporotic sheep model. Four implants coated with zoledronate and two control impla...
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Papers by Vincent Stadelmann