The Effect of Activating Fibroblast Growth Factor Receptor 3 Mutations on Osteogenic Differentiation and Ectopic Bone Formation by Human Periosteal Derived Cells

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 ▲]

A mechanobiological model of orthodontic tooth movement.

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 ▲]

Calcium phosphate scaffolds customizations for bone tissue engineering applications

Poster (2011, November 18)

An integrative model based approach to optimize calcium phosphate scaffold-stem cell combinations

Poster (2011, June 07)

Designing optimal calcium phosphate scaffold-cell combinations using an integrative model-based approach.

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 ▲]

The combined bone forming capacity of human periosteal derived cells and calcium phosphates.

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 ▲]

Mathematical modeling of cell-cell and cell-matrix adhesion in tissue engineering using continuum models

in Geffen, A. (Ed.) Cellular and Biomolecular Mechanics and Mechanobiology (2011)

Key factors in the formation of cell aggregates in tissue engineering and other fields are the cell-cell and cell-matrix interactions. Other important factors are culture conditions such as nutrient and ... [more ▼]

Key factors in the formation of cell aggregates in tissue engineering and other fields are the cell-cell and cell-matrix interactions. Other important factors are culture conditions such as nutrient and oxygen supply and the characteristics of the environment (medium versus hydrogel). As mathematical models are increasingly used to investigate biological phenomena, it is important that processes such as cell adhesion are adequately described in the models. Recently a technique was developed to incorporate cell-cell and cell-matrix adhesion in continuum models through the use of non-local terms. In this study we apply this technique to model adhesion in a cell-in-gel culture set-up often found in tissue engineering applications. We briefly describe the biological issues underlying this study and the various modeling techniques used to capture adhesive behaviour. We furthermore elaborate on the numerical techniques that were developed in the course of this study. Finally, we consider a tissue engineering model that describes the spatiotemporal evolution of the concentration of cells, matrix, hydrogel, matrix degrading enzymes and oxygen/nutrients in a cell-in-gel culture system. Sensitivity analyses indicate a clear influence of the different adhesive processes on the final cell and collagen density and distribution, demonstrating the significance of cell adhesion in tissue engineering and the potential of the proposed mathematical technique. [less ▲]

A Boolean network model of the growth plate

Poster (2010, November 26)

A mathematical model of calcium ion influence on the activity of osteogenic cells

Poster (2010, November 19)

A Boolean network model of the growth plate

Poster (2010, October 10)