References of "Van Oosterwyck, Hans"
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See detailOxygen as a critical determinant of bone fracture healing-a multiscale model.
Carlier, Aurelie; Geris, Liesbet ULg; Gastel, Nick Van et al

in Journal of theoretical biology (2015), 365

A timely restoration of the ruptured blood vessel network in order to deliver oxygen and nutrients to the fracture zone is crucial for successful bone healing. Indeed, oxygen plays a key role in the ... [more ▼]

A timely restoration of the ruptured blood vessel network in order to deliver oxygen and nutrients to the fracture zone is crucial for successful bone healing. Indeed, oxygen plays a key role in the aerobic metabolism of cells, in the activity of a myriad of enzymes as well as in the regulation of several (angiogenic) genes. In this paper, a previously developed model of bone fracture healing is further improved with a detailed description of the influence of oxygen on various cellular processes that occur during bone fracture healing. Oxygen ranges of the cell-specific oxygen-dependent processes were established based on the state-of-the art experimental knowledge through a rigorous literature study. The newly developed oxygen model is compared with previously published experimental and in silico results. An extensive sensitivity analysis was also performed on the newly introduced oxygen thresholds, indicating the robustness of the oxygen model. Finally, the oxygen model was applied to the challenging clinical case of a critical sized defect (3mm) where it predicted the formation of a fracture non-union. Further model analyses showed that the harsh hypoxic conditions in the central region of the callus resulted in cell death and disrupted bone healing thereby indicating the importance of a timely vascularization for the successful healing of a large bone defect. In conclusion, this work demonstrates that the oxygen model is a powerful tool to further unravel the complex spatiotemporal interplay of oxygen delivery, diffusion and consumption with the several healing steps, each occurring at distinct, optimal oxygen tensions during the bone repair process. [less ▲]

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See detailBringing computational models of bone regeneration to the clinic.
Carlier, Aurelie; Geris, Liesbet ULg; Lammens, Johan et al

in Wiley interdisciplinary reviews. Systems biology and medicine (2015), 7(4), 183-94

Although the field of bone regeneration has experienced great advancements in the last decades, integrating all the relevant, patient-specific information into a personalized diagnosis and optimal ... [more ▼]

Although the field of bone regeneration has experienced great advancements in the last decades, integrating all the relevant, patient-specific information into a personalized diagnosis and optimal treatment remains a challenging task due to the large number of variables that affect bone regeneration. Computational models have the potential to cope with this complexity and to improve the fundamental understanding of the bone regeneration processes as well as to predict and optimize the patient-specific treatment strategies. However, the current use of computational models in daily orthopedic practice is very limited or inexistent. We have identified three key hurdles that limit the translation of computational models of bone regeneration from bench to bed side. First, there exists a clear mismatch between the scope of the existing and the clinically required models. Second, most computational models are confronted with limited quantitative information of insufficient quality thereby hampering the determination of patient-specific parameter values. Third, current computational models are only corroborated with animal models, whereas a thorough (retrospective and prospective) assessment of the computational model will be crucial to convince the health care providers of the capabilities thereof. These challenges must be addressed so that computational models of bone regeneration can reach their true potential, resulting in the advancement of individualized care and reduction of the associated health care costs. WIREs Syst Biol Med 2015, 7:183-194. doi: 10.1002/wsbm.1299 For further resources related to this article, please visit the WIREs website. CONFLICT OF INTEREST: The authors have declared no conflicts of interest for this article. [less ▲]

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See detailBringing regenerating tissues to life: the importance of angiogenesis in tissue engineering
Carlier, Aurélie ULg; Van Gastel, Nick; Geris, Liesbet ULg et al

Poster (2014, March 11)

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See detailSize does matter: an integrative in vivo-in silico approach for the treatment of critical size bone defects.
Carlier, Aurelie; van Gastel, Nick; Geris, Liesbet ULg et al

in PLoS computational biology (2014), 10(11), 1003888

Although bone has a unique restorative capacity, i.e., it has the potential to heal scarlessly, the conditions for spontaneous bone healing are not always present, leading to a delayed union or a non ... [more ▼]

Although bone has a unique restorative capacity, i.e., it has the potential to heal scarlessly, the conditions for spontaneous bone healing are not always present, leading to a delayed union or a non-union. In this work, we use an integrative in vivo-in silico approach to investigate the occurrence of non-unions, as well as to design possible treatment strategies thereof. The gap size of the domain geometry of a previously published mathematical model was enlarged in order to study the complex interplay of blood vessel formation, oxygen supply, growth factors and cell proliferation on the final healing outcome in large bone defects. The multiscale oxygen model was not only able to capture the essential aspects of in vivo non-unions, it also assisted in understanding the underlying mechanisms of action, i.e., the delayed vascularization of the central callus region resulted in harsh hypoxic conditions, cell death and finally disrupted bone healing. Inspired by the importance of a timely vascularization, as well as by the limited biological potential of the fracture hematoma, the influence of the host environment on the bone healing process in critical size defects was explored further. Moreover, dependent on the host environment, several treatment strategies were designed and tested for effectiveness. A qualitative correspondence between the predicted outcomes of certain treatment strategies and experimental observations was obtained, clearly illustrating the model's potential. In conclusion, the results of this study demonstrate that due to the complex non-linear dynamics of blood vessel formation, oxygen supply, growth factor production and cell proliferation and the interactions thereof with the host environment, an integrative in silico-in vivo approach is a crucial tool to further unravel the occurrence and treatments of challenging critical sized bone defects. [less ▲]

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See detailIn silico biology of bone regeneration inside calcium phosphate scaffolds
Carlier, Aurélie ULg; Van Oosterwyck, Hans; Geris, Liesbet ULg

in Tissue Engineering: Computer Modeling, Biofabrication and Cell Behavior (2014)

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See detailOxygen: a critical component of critically sized defects
Carlier, Aurélie ULg; Van Gastel, Nick; Geris, Liesbet ULg et al

Poster (2013, December 19)

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See detailA mathematical model of the role of oxygen during normal and delayed fracture repair
Carlier, Aurélie ULg; Van Gastel, Nick; Carmeliet, Geert et al

Conference (2013, October 24)

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See detailA gene regulatory network model evaluating the impact of individual factors in the hypertrophic switch
Kerkhofs, Johan ULg; Van Oosterwyck, Hans; Geris, Liesbet ULg

Conference (2013, September 11)

Chondrocytes undergoing hypertrophy show a major switch in phenotype underlied by a change in expression from the chondrocyte master gene, Sox9, to the osteoblastic one, Runx2. Strategies to stimulate or ... [more ▼]

Chondrocytes undergoing hypertrophy show a major switch in phenotype underlied by a change in expression from the chondrocyte master gene, Sox9, to the osteoblastic one, Runx2. Strategies to stimulate or inhibit this switch are of use in bone and cartilage tissue engineering respectively, as well as in the prevention of ectopic hypertrophy in osteoarthritis. We have constructed a literature based network comprised of 46 nodes and 161 interactions shown to play a part in chondrocyte hypertrophy. Network dynamics are simulated in discrete time through random updating by the use of additive functions to determine each node’s value. Furthermore, each species is represented by a fast variable (activity level, as determined by post translation modifications) which is assumed to be in equilibrium with a slow variable (mRNA) at all times. Through a Monte Carlo approach the importance of each node in the stability of chondrocytic phenotypes (proliferating, hypertrophic) is assessed in random initial conditions. A perturbation analysis of the stable states is used to determine the transition likelihood between states and the influence of individual nodes in this transition as a second measure of stability. Our results show that the hypertrophic state, marked by Runx2 expression, has a larger attractor basin and is more stable to perturbation than the proliferative state characterized by Sox9. The added time resolution seems to favour the Runx2 phenotype. The results for single nodes in overexpression or knockout simulations show a certain asymmetry, indicating that factors that are necessary for maintaining a certain phenotype are not necessarily useful in inducing it. [less ▲]

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See detailTo heal or not to heal: modeling the influence of oxygen during fracture healing.
Carlier, Aurélie ULg; Geris, Liesbet ULg; Van Oosterwyck, Hans

Conference (2013, September 11)

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See detailA Gene Regulatory Network Model to Assess the Stability of the Cartilage Phenotype
Kerkhofs, Johan ULg; Van Oosterwyck, Hans; Geris, Liesbet ULg

Poster (2013, August 29)

Introduction Chondrocyte hypertrophy entails the switching of a genetic program driven by Sox9 to one under control of the osteoblast master regulator Runx2. The switch is a prerequisite step in the bone ... [more ▼]

Introduction Chondrocyte hypertrophy entails the switching of a genetic program driven by Sox9 to one under control of the osteoblast master regulator Runx2. The switch is a prerequisite step in the bone forming process (endochondral ossification) during development and in postnatal fracture repair of larger bone defects. However, this switch can also be detrimental in tissue engineered cartilage constructs and in osteoarthritis development [Saito, 2010]. Therefore, a detailed model of the pathways that can facilitate, or inhibit, this phenotypic switch will lead to a more profound understanding of these processes and provide hints as to how to manipulate them. Methods The model formalism accommodates the qualitative information that is typically available in developmental studies. The literature based network comprises 46 nodes and 161 interactions, shown to be important in endochondral ossification. To simulate network dynamics in discrete time the normalized value of each gene is determined by additive functions where all interactions are assumed to be equally powerful. Furthermore, each species is represented by a fast variable (activity level, as determined by post translation modifications) which is assumed to be in equilibrium with a slow variable (mRNA) at all times. Through a Monte Carlo approach the importance of each node in the stability of chondrocytic phenotypes (proliferating, hypertrophic) is assessed in random initial conditions. A perturbation analysis of the stable states is used to determine the transition likelihood between them as a second measure of stability. Results Both measures of stability indicate that the hypertrophic (Runx2 driven) state is more stable than the proliferating one driven by Sox9. The results for the second measure are given in Fig.1. This higher stability seems to be partly conferred by faster reactions that favour the hypertrophic phenotype. In addition, the results point out that some transcription factors are necessary for the induction of a certain phenotype, whereas other transcription factors are required to maintain the phenotype, but are not necessary capable of inducing it. Discussion These results may relate to the difficulty experienced by researchers in maintaining a stable cartilage phenotype in culture and the occurrence of ectopic hypertrophy in osteoarthritis. By analysing the effect of changes to individual nodes, strategies to stabilise the proliferating phenotype can be developed. Overall, the model allows the importance of several important factors in the fate decision of mesenchymal cells to be quantitatively assessed based mainly on topological information. [less ▲]

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See detailModeling the influence of oxygen in delayed bone fracture healing.
Carlier, Aurélie ULg; Geris, Liesbet ULg; Van Oosterwyck, Hans

Conference (2013, August 25)

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See detailA computational Model to Assess the Contribution of Growth Factors to Phenotype Stability in Chondrocytes
Kerkhofs, Johan ULg; Van Oosterwyck, Hans

Conference (2013, June 17)

Cell-based tissue engineering constructs are an interesting expansion of the surgeon’s toolkit in treating long bone defects. However, the outcome of interventions with these constructs suffers from high ... [more ▼]

Cell-based tissue engineering constructs are an interesting expansion of the surgeon’s toolkit in treating long bone defects. However, the outcome of interventions with these constructs suffers from high variability barring their regular appearance in the clinic, in no small part due to the inter-patient variability in cell behaviour. In the paradigm of ‘developmental engineering’ a solution to this problem is envisioned by mimicking robust developmental processes in combination with a rigorous analysis thereof through the construction of computational models. From our knowledge of developmental biology we can form a computational model to facilitate understanding of how growth factors and transcription factors influence cell fate decisions in the growth plate and consequently answer the question whether – and how – they can boost bone healing. The model presented in this study includes 46 factors and 146 interactions between them. The dynamics of the system were simulated in a simplified manner that differentiates between slow and fast interactions. Through a Monte Carlo approach the importance of each factor in the stability of chondrocytic phenotypes (proliferating, hypertrophic) is assessed. The hypertrophic state was found to be more stable than that of the proliferating chondrocyte. This higher stability in random initial conditions seems to be conferred by faster reactions that favor the hypertrophic phenotype. Overall, the model allows the importance of several important factors in the fate decision of chondrocytes to be quantitatively assessed and can make suggestions as to how an in vitro bone forming process could be steered. [less ▲]

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See detailA multiscale model of the influence of oxygen during bone fracture healing.
Carlier, Aurélie ULg; Geris, Liesbet ULg; Van Oosterwyck, Hans

Poster (2013, April 03)

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See detailValidation of a finite element model of a unilateral external fixator in a rabbit tibia defect model.
Karunratanakul, Kavin; Kerckhofs, Greet ULg; Lammens, Johan et al

in Medical engineering & physics (2013), 35(7), 1037-43

In case of large segmental defects in load-bearing bones, an external fixator is used to provide mechanical stability to the defect site. The overall stiffness of the bone-fixator system is determined not ... [more ▼]

In case of large segmental defects in load-bearing bones, an external fixator is used to provide mechanical stability to the defect site. The overall stiffness of the bone-fixator system is determined not only by the fixator design but also by the way the fixator is mounted to the bone. This stiffness is an important factor as it will influence the biomechanical environment to which tissue engineering scaffolds and regenerating tissues are exposed. A finite element (FE) model can be used to predict the system stiffness. The goal of this study is to develop and validate a 3D anatomical FE model of a bone-fixator system which includes a previously developed unilateral external fixator for a large segmental defect model in the rabbit tibia. It was hypothesized that the contact interfaces between bone and fixator screws play a major role for the prediction of the stiffness. In vitro mechanical testing was performed in order to measure the axial stiffness of cortical bone from mid-shaft rabbit tibiae and of the tibia-fixator system, as well as the bending stiffness of individual fixator screws, inserted in bone. muCT-based case-specific FE models of cortical bone and SCREW-BONE specimens were created to simulate the corresponding mechanical test set-ups. The Young's modulus of rabbit cortical bone as well as appropriate screw-bone contact settings were derived from those FE models. We then used the derived settings in an FE model of the tibia-fixator system. The difference between the FE predicted and measured axial stiffness of the tibia-fixator system was reduced from 117.93% to 7.85% by applying appropriate screw-bone contact settings. In conclusion, this study shows the importance of screw-bone contact settings for an accurate fixator stiffness prediction. The validated FE model can further be used as a tool for virtual mechanical testing in the design phase of new tissue engineering scaffolds and/or novel patient-specific external fixation devices. [less ▲]

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See detailFluorescent oxygen sensitive microbead incorporation for measuring oxygen tension in cell aggregates.
Lambrechts, Dennis; Roeffaers, Maarten; Kerckhofs, Greet ULg et al

in Biomaterials (2013), 34(4), 922-9

Molecular oxygen is a main regulator of various cell functions. Imaging methods designed as screening tools for fast, in situ, 3D and non-interfering measurement of oxygen tension in the cellular ... [more ▼]

Molecular oxygen is a main regulator of various cell functions. Imaging methods designed as screening tools for fast, in situ, 3D and non-interfering measurement of oxygen tension in the cellular microenvironment would serve great purpose in identifying and monitoring this vital and pivotal signalling molecule. We describe the use of dual luminophore oxygen sensitive microbeads to measure absolute oxygen concentrations in cellular aggregates. Stable microbead integration, a prerequisite for their practical application, was ensured by a site-specific delivery method that is based on the interactions between streptavidin and biotin. The spatial stability introduced by this method allowed for long term measurements of oxygen tension without interfering with the cell aggregation process. By making multiple calibration experiments we further demonstrated the potential of these sensors to measure local oxygen tension in optically dense cellular environments. [less ▲]

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See detailTo heal or not to heal: a multiscale model of the influence of oxygen during bone fracture healing.
Carlier, Aurélie ULg; Geris, Liesbet ULg; Van Oosterwyck, Hans

Poster (2012, October 24)

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See detailA multiscale model of sprouting angiogenesis during fracture healing.
Carlier, Aurélie ULg; Geris, Liesbet ULg; Van Oosterwyck, Hans

Conference (2012, September 18)

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See detailA Dynamic Graph Model of Endochondral Ossification can assess the Importance of Biological Actors in Differentiation
Kerkhofs, Johan ULg; Van Oosterwyck, Hans; Geris, Liesbet ULg

Conference (2012, September 18)

Cell-based tissue engineering constructs are a promising avenue for the treatment of long bone defects since they provide the primordial ingredients for bone regeneration. The construct provides the ... [more ▼]

Cell-based tissue engineering constructs are a promising avenue for the treatment of long bone defects since they provide the primordial ingredients for bone regeneration. The construct provides the appropriate micro-environment through the carrier, cells to form tissue and chemical cues to kick start the natural bone forming process. Clearly this approach will benefit from a more comprehensive appreciation of how cell populations and the microenvironment provided by the carrier can impact on bone formation in all its complexities. A cornucopia of studies of developmental biology have revealed many biological actors that together form a central network that orchestrates cell behaviour during this process and assures its robustness. This knowledge can be brought to bear specifically in the form of a mathematical model of endochondral ossification, the dominant type of ossification. This model can facilitate the understanding of how growth factors and transcription factors influence cell fate decisions and consequently answer the question whether they can boost bone healing. The model formalism accommodates the qualitative information that is typically available in developmental studies. The network comprises 46 nodes and 161 interactions, shown to be important in endochondral ossification. To simulate network dynamics in discrete time the normalized value of each gene is determined by additive functions where all interactions are assumed to be equally powerful. Furthermore, each species is represented by a fast variable (activity level, as determined by post translation modifications) which is assumed to be in equilibrium with a slow variable (mRNA) at all times. Through a Monte Carlo approach the importance of each node in the stability of chondrocytic phenotypes (proliferating, hypertrophic) is assessed. The hypertrophic state, driven by Runx2, is more stable than the proliferating chondrocyte. This higher stability seems to be conferred by faster reactions that favor the hypertrophic phenotype. In addition, the results point out that some transcription factors are necessary for the induction of a certain phenotype, whereas other transcription factors are required to maintain the phenotype, but are not necessary capable of inducing it. Overall, the model allows the importance of several important factors in the fate decision of mesenchymal cells to be quantitatively assessed based mainly on topological information. [less ▲]

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See detailMultiscale modeling of in the influence of oxygen during bone fracture healing.
Carlier, Aurélie ULg; Van Gastel, Nick; Carmeliet, Geert et al

Poster (2012, September 17)

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See detailMultiscale modeling of sprouting angiogenesis: tip cells are selected for the top.
Carlier, Aurélie ULg; Geris, Liesbet ULg; Van Oosterwyck, Hans

Poster (2012, September 05)

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