Bridging the Gap: A Theoretical Model of Mechanotransduction Through ERK Signalling
Kerkhofs, Johan ; Geris, Liesbet ; et al
Conference (2012, July 02)Detailed reference viewed: 4 (0 ULg)
Tip cells at the top: a multiscale model of sprouting angiogenesis.
Carlier, Aurélie ; Geris, Liesbet ;
Conference (2012, July 01)Detailed reference viewed: 12 (1 ULg)
Relating the Chondrocyte Gene Network to Growth Plate Morphology: From Genes to Phenotype
Kerkhofs, Johan ; ; et al
in PLoS ONE (2012)
During endochondral ossification, chondrocyte growth and differentiation is controlled by many local signalling pathways. Due to crosstalks and feedback mechanisms, these interwoven pathways display a ... [more ▼]
During endochondral ossification, chondrocyte growth and differentiation is controlled by many local signalling pathways. Due to crosstalks and feedback mechanisms, these interwoven pathways display a network like structure. In this study, a large-scale literature based logical model of the growth plate network was developed. The network is able to capture the different states (resting, proliferating and hypertrophic) that chondrocytes go through as they progress within the growth plate. In a first corroboration step, the effect of mutations in various signalling pathways of the growth plate network was investigated. [less ▲]Detailed reference viewed: 24 (8 ULg)
Coupling Cell Mechanics and Intracellular Signalling: Mechanotransduction through ERK
Kerkhofs, Johan ; Geris, Liesbet ; et al
in Middleton, John (Ed.) The Proceedings of the 10th International Symposium on Computer Methods in Biomechanics and Biomedical Engineering. Hotel Berlin, Berlin, Germany, April 7th – 11th, 2012 pages:0-0 (2012, April 12)Detailed reference viewed: 3 (1 ULg)
Tip cells at the top: multiscale modeling of angiogenesis during fracture healing
Carlier, Aurélie ; Geris, Liesbet ;
in Computer Methods in Biomechanics and Biomedical Engineering (CMBBE) - Proceedings (2012, April)Detailed reference viewed: 34 (10 ULg)
MOSAIC: a multiscale model of osteogenesis and sprouting angiogenesis with lateral inhibition of endothelial cells.
Carlier, Aurélie ; Geris, Liesbet ; et al
in PLoS Computational Biology (2012), 8(10), 1002724
The healing of a fracture depends largely on the development of a new blood vessel network (angiogenesis) in the callus. During angiogenesis tip cells lead the developing sprout in response to ... [more ▼]
The healing of a fracture depends largely on the development of a new blood vessel network (angiogenesis) in the callus. During angiogenesis tip cells lead the developing sprout in response to extracellular signals, amongst which vascular endothelial growth factor (VEGF) is critical. In order to ensure a correct development of the vasculature, the balance between stalk and tip cell phenotypes must be tightly controlled, which is primarily achieved by the Dll4-Notch1 signaling pathway. This study presents a novel multiscale model of osteogenesis and sprouting angiogenesis, incorporating lateral inhibition of endothelial cells (further denoted MOSAIC model) through Dll4-Notch1 signaling, and applies it to fracture healing. The MOSAIC model correctly predicted the bone regeneration process and recapitulated many experimentally observed aspects of tip cell selection: the salt and pepper pattern seen for cell fates, an increased tip cell density due to the loss of Dll4 and an excessive number of tip cells in high VEGF environments. When VEGF concentration was even further increased, the MOSAIC model predicted the absence of a vascular network and fracture healing, thereby leading to a non-union, which is a direct consequence of the mutual inhibition of neighboring cells through Dll4-Notch1 signaling. This result was not retrieved for a more phenomenological model that only considers extracellular signals for tip cell migration, which illustrates the importance of implementing the actual signaling pathway rather than phenomenological rules. Finally, the MOSAIC model demonstrated the importance of a proper criterion for tip cell selection and the need for experimental data to further explore this. In conclusion, this study demonstrates that the MOSAIC model creates enhanced capabilities for investigating the influence of molecular mechanisms on angiogenesis and its relation to bone formation in a more mechanistic way and across different time and spatial scales. [less ▲]Detailed reference viewed: 16 (3 ULg)
A visco-elastic model for the prediction of orthodontic tooth movement.
Van Schepdael, An ; ; Geris, Liesbet et al
in Computer Methods in Biomechanics & Biomedical Engineering (2012)
This study presents a biomechanical model of orthodontic tooth movement. Although such models have already been presented in the literature, most of them incorporate computationally expensive finite ... [more ▼]
This study presents a biomechanical model of orthodontic tooth movement. Although such models have already been presented in the literature, most of them incorporate computationally expensive finite elements (FE) methods to determine the strain distribution in the periodontal ligament (PDL). In contrast, the biomechanical model presented in this work avoids the use of FE methods. The elastic deformation of the PDL is modelled using an analytical approach, which does not require setting up a 3D model of the tooth. The duration of the lag phase is estimated using the calculated hydrostatic stresses, and bone remodelling is predicted by modelling the alveolar bone as a viscous material. To evaluate the model, some typically used motion patterns were simulated and a sensitivity analysis was carried out on the parameters. Results show that despite some shortcomings, the model is able to describe commonly used motion patterns in orthodontic tooth movement, in both single- and multi-rooted teeth. [less ▲]Detailed reference viewed: 15 (1 ULg)
Current views on calcium phosphate osteogenicity and the translation into effective bone regeneration strategies.
; Carlier, Aurélie ; et al
in Acta Biomaterialia (2012), 8(11), 3876-87
Calcium phosphate (CaP) has traditionally been used for the repair of bone defects because of its strong resemblance to the inorganic phase of bone matrix. Nowadays, a variety of natural or synthetic CaP ... [more ▼]
Calcium phosphate (CaP) has traditionally been used for the repair of bone defects because of its strong resemblance to the inorganic phase of bone matrix. Nowadays, a variety of natural or synthetic CaP-based biomaterials are produced and have been extensively used for dental and orthopaedic applications. This is justified by their biocompatibility, osteoconductivity and osteoinductivity (i.e. the intrinsic material property that initiates de novo bone formation), which are attributed to the chemical composition, surface topography, macro/microporosity and the dissolution kinetics. However, the exact molecular mechanism of action is unknown. This review paper first summarizes the most important aspects of bone biology in relation to CaP and the mechanisms of bone matrix mineralization. This is followed by the research findings on the effects of calcium (Ca(2)(+)) and phosphate (PO(4)(3)(-)) ions on the migration, proliferation and differentiation of osteoblasts during in vivo bone formation and in vitro culture conditions. Further, the rationale of using CaP for bone regeneration is explained, focusing thereby specifically on the material's osteoinductive properties. Examples of different material forms and production techniques are given, with the emphasis on the state-of-the art in fine-tuning the physicochemical properties of CaP-based biomaterials for improved bone induction and the use of CaP as a delivery system for bone morphogenetic proteins. The use of computational models to simulate the CaP-driven osteogenesis is introduced as part of a bone tissue engineering strategy in order to facilitate the understanding of cell-material interactions and to gain further insight into the design and optimization of CaP-based bone reparative units. Finally, limitations and possible solutions related to current experimental and computational techniques are discussed. [less ▲]Detailed reference viewed: 15 (1 ULg)
Mechanisms of ectopic bone formation by human osteoprogenitor cells on CaP biomaterial carriers.
; ; et al
in Biomaterials (2012)
Stem cell-based strategies for bone regeneration, which use calcium phosphate (CaP)-based biomaterials in combination with developmentally relevant progenitor populations, have significant potential for ... [more ▼]
Stem cell-based strategies for bone regeneration, which use calcium phosphate (CaP)-based biomaterials in combination with developmentally relevant progenitor populations, have significant potential for clinical repair of skeletal defects. However, the exact mechanism of action and the stem cell-host-material interactions are still poorly understood. We studied if pre-conditioning of human periosteum-derived cells (hPDCs) in vitro could enhance, in combination with a CaP-based biomaterial carrier, ectopic bone formation in vivo. By culturing hPDCs in a biomimetic calcium (Ca(2+)) and phosphate (P(i)) enriched culture conditions, we observed an enhanced cell proliferation, decreased expression of mesenchymal stem cell (MSC) markers and upregulation of osteogenic genes including osterix, Runx2, osteocalcin, osteopontin, and BMP-2. However, the in vitro pre-conditioning protocols were non-predictive for in vivo ectopic bone formation. Surprisingly, culturing in the presence of Ca(2+) and P(i) supplements resulted in partial or complete abrogation of in vivo ectopic bone formation. Through histological, immunohistochemical and microfocus X-ray computed tomography (muCT) analysis of the explants, we found that in situ proliferation, collagen matrix deposition and the mediation of osteoclastic activity by hPDCs are associated to their ectopic bone forming capacity. These data were validated by the multivariate analysis and partial least square regression modelling confirming the non-predictability of in vitro parameters on in vivo ectopic bone formation. Our series of experiments provided further insights on the stem cell-host-material interactions that govern in vivo ectopic bone induction driven by hPDCs on CaP-based biomaterials. [less ▲]Detailed reference viewed: 22 (5 ULg)
The Effect of Activating Fibroblast Growth Factor Receptor 3 Mutations on Osteogenic Differentiation and Ectopic Bone Formation by Human Periosteal Derived Cells
; ; et al
in Journal of Tissue Science & Engineering (2012), 2
Activating mutations in Fibroblast Growth Factor Receptor 3 (FGFR3) have previously been shown to cause skeletal dysplasias through their effect on growth plate chondrocytes. However, the effect of FGFR3 ... [more ▼]
Activating mutations in Fibroblast Growth Factor Receptor 3 (FGFR3) have previously been shown to cause skeletal dysplasias through their effect on growth plate chondrocytes. However, the effect of FGFR3 mutations on bone progenitor cells may differ. The objective of this study was to investigate the effect of specific activating FGFR3 mutations on ectopic in vivo bone formation by periosteal derived cells (PDCs) seeded on calcium phosphate/ collagen scaffolds. PDCs were isolated from hypochondroplasic (N540K mutation) and achondroplasic (G380R mutation) patients, along with age/sex matched controls. These cells were characterised in vitro for proliferation, osteogenic differentiation, FGFR3 signalling and in vivo bone formation. Subsequently, empirical modelling was used to find correlations between in vivo formed bone and in vitro cell behaviour. These data showed that in contrast to the G380R mutation, which produced no bone, the N540K mutation induced significant ectopic bone formation on specific carriers. This allowed correlation between percentage of induced bone formation to elevated in vitro proliferation and differentiation. Correlating osteogenic markers included Collagen type 1, alkaline phosphatase and osteocalcin. Enhanced proliferation was attributed to increased phosphorylation of Erk-1/2. This study highlights the importance of FGFR3 in periosteal cell differentiation and also indicates it potential for targeted tissue engineering strategies. [less ▲]Detailed reference viewed: 31 (9 ULg)
A mathematical model of adult subventricular neurogenesis.
; ; et al
in Journal of the Royal Society, Interface (2012)
Neurogenesis has been the subject of active research in recent years and many authors have explored the phenomenology of the process, its regulation and its purported purpose. Recent developments in ... [more ▼]
Neurogenesis has been the subject of active research in recent years and many authors have explored the phenomenology of the process, its regulation and its purported purpose. Recent developments in bioluminescent imaging (BLI) allow direct in vivo imaging of neurogenesis, and in order to interpret the experimental results, mathematical models are necessary. This study proposes such a mathematical model that describes adult mammalian neurogenesis occurring in the subventricular zone and the subsequent migration of cells through the rostral migratory stream to the olfactory bulb (OB). This model assumes that a single chemoattractant is responsible for cell migration, secreted both by the OB and in an endocrine fashion by the cells involved in neurogenesis. The solutions to the system of partial differential equations are compared with the physiological rodent process, as previously documented in the literature and quantified through the use of BLI, and a parameter space is described, the corresponding solution to which matches that of the rodent model. A sensitivity analysis shows that this parameter space is stable to perturbation and furthermore that the system as a whole is sloppy. A large number of parameter sets are stochastically generated, and it is found that parameter spaces corresponding to physiologically plausible solutions generally obey constraints similar to the conditions reported in vivo. This further corroborates the model and its underlying assumptions based on the current understanding of the investigated phenomenon. Concomitantly, this leaves room for further quantitative predictions pertinent to the design of future proposed experiments. [less ▲]Detailed reference viewed: 12 (3 ULg)
A mechanobiological model of orthodontic tooth movement.
; ; Geris, Liesbet
in Biomechanics & Modeling in Mechanobiology (2012)
Orthodontic tooth movement is achieved by the process of repeated alveolar bone resorption on the pressure side and new bone formation on the tension side. In order to optimize orthodontic treatment, it ... [more ▼]
Orthodontic tooth movement is achieved by the process of repeated alveolar bone resorption on the pressure side and new bone formation on the tension side. In order to optimize orthodontic treatment, it is important to identify and study the biological processes involved. This article presents a mechanobiological model using partial differential equations to describe cell densities, growth factor concentrations, and matrix densities occurring during orthodontic tooth movement. We hypothesize that such a model can predict tooth movement based on the mechanobiological activity of cells in the PDL. The developed model consists of nine coupled non-linear partial differential equations, and two distinct signaling pathways were modeled: the RANKL-RANK-OPG pathway regulating the communication between osteoblasts and osteoclasts and the TGF-beta pathway mediating the differentiation of mesenchymal stem cells into osteoblasts. The predicted concentrations and densities were qualitatively validated by comparing the results to experiments reported in the literature. In the current form, the model supports our hypothesis, as it is capable of conceptually simulating important features of the biological interactions in the alveolar bone-PDL complex during orthodontic tooth movement. [less ▲]Detailed reference viewed: 18 (3 ULg)
Calcium phosphate scaffolds customizations for bone tissue engineering applications
Carlier, Aurélie ; ; et al
Poster (2011, November 18)Detailed reference viewed: 16 (4 ULg)
A Boolean network approach to developmental engineering
Kerkhofs, Johan ; ; et al
Conference (2011, June 13)Detailed reference viewed: 10 (0 ULg)
An integrative model based approach to optimize calcium phosphate scaffold-stem cell combinations
Carlier, Aurélie ; ; et al
Poster (2011, June 07)Detailed reference viewed: 6 (0 ULg)
Optimization of calcium phosphate scaffold-cell combinations using an integrative model based approach
Carlier, Aurélie ; ; et al
(2011, June 03)Detailed reference viewed: 9 (2 ULg)
Designing optimal calcium phosphate scaffold-cell combinations using an integrative model-based approach.
Carlier, Aurélie ; ; et al
in Acta Biomaterialia (2011), 7(10), 3573-85
Bone formation is a very complex physiological process, involving the participation of many different cell types and regulated by countless biochemical, physical and mechanical factors, including ... [more ▼]
Bone formation is a very complex physiological process, involving the participation of many different cell types and regulated by countless biochemical, physical and mechanical factors, including naturally occurring or synthetic biomaterials. For the latter, calcium phosphate (CaP)-based scaffolds have proven to stimulate bone formation, but at present still result in a wide range of in vivo outcomes, which is partly related to the suboptimal use and combination with osteogenic cells. To optimize CaP scaffold selection and make their use in combination with cells more clinically relevant, this study uses an integrative approach in which mathematical modeling is combined with experimental research. This paper describes the development and implementation of an experimentally informed bioregulatory model of the effect of calcium ions released from CaP-based biomaterials on the activity of osteogenic cells and mesenchymal stem cell driven ectopic bone formation. The amount of bone formation predicted by the mathematical model corresponds to the amount measured experimentally under similar conditions. Moreover, the model is also able to qualitatively predict the experimentally observed impaired bone formation under conditions such as insufficient cell seeding and scaffold decalcification. A strategy was designed in silico to overcome the negative influence of a low initial cell density on the bone formation process. Finally, the model was applied to design optimal combinations of calcium-based biomaterials and cell culture conditions with the aim of maximizing the amount of bone formation. This work illustrates the potential of mathematical models as research tools to design more efficient and cell-customized CaP scaffolds for bone tissue engineering applications. [less ▲]Detailed reference viewed: 38 (15 ULg)
Continuum-level modelling of cellular adhesion and matrix production in aggregates.
Geris, Liesbet ; ;
in Computer Methods in Biomechanics & Biomedical Engineering (2011), 14(5), 403-10
Key regulators in tissue-engineering processes such as cell culture and cellular organisation are the cell-cell and cell-matrix interactions. As mathematical models are increasingly applied to investigate ... [more ▼]
Key regulators in tissue-engineering processes such as cell culture and cellular organisation are the cell-cell and cell-matrix interactions. As mathematical models are increasingly applied to investigate biological phenomena in the biomedical field, it is important, for some applications, that these models incorporate an adequate description of cell adhesion. This study describes the development of a continuum model that represents a cell-in-gel culture system used in bone-tissue engineering, namely that of a cell aggregate embedded in a hydrogel. Cell adhesion is modelled through the use of non-local (integral) terms in the partial differential equations. The simulation results demonstrate that the effects of cell-cell and cell-matrix adhesion are particularly important for the survival and growth of the cell population and the production of extracellular matrix by the cells, concurring with experimental observations in the literature. [less ▲]Detailed reference viewed: 10 (2 ULg)
The combined bone forming capacity of human periosteal derived cells and calcium phosphates.
; Geris, Liesbet ; et al
in Biomaterials (2011), 32(19), 4393-405
Current knowledge suggests that the periosteum, a fibrous tissue which covers the surface of all bones, contains a population of progenitor cells which mediate the repair of bone defects. In an effort to ... [more ▼]
Current knowledge suggests that the periosteum, a fibrous tissue which covers the surface of all bones, contains a population of progenitor cells which mediate the repair of bone defects. In an effort to optimise the utilisation of this source of cells for bone engineering, herein we describe the rational selection of calcium phosphate (CaP) containing materials, based on biomaterial properties, and evaluation of their combined bone forming capacity. Five different commercially available orthopaedic 3D matrices composed of CaP particles in an open collagen network (NuOss, CopiOs, Bio-Oss((R)), Collagraft and Vitoss((R))) were evaluated in vitro and in vivo with human periosteal derived cells (hPDCs). It was found that the cell-material combinations behaved quite differently in vivo, despite apparent in vitro similarities in gene expression profiles. Bone formation was highest within the NuOss/hPDC implant at 13.03%, which also contained the highest incidence of bone marrow formation. The bone formed in this implant was chimeric with approximately 65% originating from implanted cells. Upon analysis of human specific gene expression, although it was found that predominantly osteogenic differentiation was observed within NuOss/hPDC implants, a lesser induction of chondrogenic genes was also observed. The formation of a cartilage intermediate was confirmed by histology. Additionally the NuOss/hPDC implant integrated into the mouse environment with apparent active scaffold resorption. This study demonstrates the importance of matching a cell support/biological matrix with a cell type and subsequently has outlined parameters which can be used for the rational selection of biomaterials for bone engineering. [less ▲]Detailed reference viewed: 23 (0 ULg)