Mechanobiology and tissue engineering
- A combined computational and experimental approach for optimizing in vitro culturing of bone engineering construct
- The importance of biomechanics towards the reconstruction of large defects in load bearing bones by means of soft biological scaffolds
- Development of Tools for Quality Control of Combination Product Design and Manufacturing for Use in Skeletal Tissue Engineering Applications
- Modelling of gene networks for steering of biomimetic production processes in tissue engineering
- Multi-scale modeling in bone tissue engineering: from biomaterials to intracellular signaling cascades via the cell
- How do stem cells interact with their extracellular matrix mechanically and what are its mechanobiological implications for skeletal tissue engineering? A computational modelling approach informed by in-vitro experiments
A combined computational and experimental approach for optimizing in vitro culturing of bone engineering constructs
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Bone tissue engineering makes use of osteoprogenitor cells that are seeded onto a scaffold and cultured in a (perfusion) bioreactor. Perfusion conditions during in vitro culturing will influence flow induced mechanical stimuli and nutrient conditions (like oxygen concentration) inside the scaffold, which in turn affect in vitro proliferation and osteogenic differentiation. The project investigates the effect of the fluid dynamic environment and more exactly of the wall shear stress (WSS) and oxygen concentration (pO2). This will be done by means of a combined experimental and computational approach. Experimental results will serve as input for the establishment of a computational modeling platform in order to predict cell dynamics in porous scaffolds based on local WSS and pO2. |
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The importance of biomechanics towards the reconstruction of large defects in load bearing bones
The mechanical environment is known to play an important role for the successful reconstruction of large bone defects in load-bearing bones. Quantification of this environment is needed, in order to increase our quantitative understanding of its influence, to improve tissue engineering strategies, and to bring these treatment strategies closer towards a clinical application. The aim of this research is to develop and apply a methodology to quantify the in vivo mechanical environment of a tissue engineering construct in load-bearing bones. In a next step, treatment strategies will be developed that enable to successfully apply promising constructs (i.e. constructs that lead to ectopic bone formation in non load-bearing environments) in load-bearing situations. To this end, in vivo experiments will be designed that investigate the effect of the (mechanical) stabilisation and fixation on bone induction / ingrowth in scaffolds, used to reconstruct a segmental bone defect.
Development of Tools for Quality Control of Combination Product Design and Manufacturing for Use in Skeletal Tissue Engineering Applications
Musculoskeletal conditions represent a major economic burden on individuals, health systems and social care systems. To treat such disorders, advanced cell therapy products have been developed. However, due to cell delivery control and scaling limitations associated with these cell products, research is now ongoing towards combination products (CP), defined as cells combined with a suitable carrier biomaterial, the latter being a scaffold (e.g. hydrogels or open porous materials) that provides a structural template to fill the tissue lesion that is supportive of the envisioned cell behaviour. The main aims of this PhD on the one hand are to provide a quality control (QC) procedure to assess the outcome of a given cell-scaffold combination, using biologically relevant parameters. To achieve this, close collaboration with the R&D division of TiGenix is established to provide non-invasive imaging tools and the necessary biological know-how. On the other hand a manufacturing protocol will be developed that must lead to a quality assured CP and that complies with the general Good Manufacturing Process (GMP) requirements. For this manufacturing process great appeal can be made to existing knowledge and tools (such as bioreactors and mathematical models) available within the K.U.Leuven Prometheus division. Finally the established QC procedure will be translated to evaluate the behaviour of the implanted CP, in vitro and in vivo.
Modelling of gene networks for steering of biomimetic production processes in tissue engineering
This project aims to increase the predictability and the consistency of the behaviour of TE products by means of the development and application of Boolean gene network models. Such models can assist in establishing, optimising and steering biomimetic TE production processes. A Boolean model is developed to identify and elucidate vital developmental signalling pathways and their interactions in the developmental process of endochondral ossification. Once the key players as well as genes that can influence them are highlighted (in vivo), their expression will be investigated by in vitro cultures of several cell types. The in vitro process will be assessed on whether, and to what extent, the desired developmental pathways (i.e. endochondral ossification as described by the in vivo Boolean model) are being followed. The characterisation of the cell population, using the Boolean model, would give an indication of the cell state and their ability to induce ossification in vivo, and in this regard the parameters are useful to control and observe the in vitro process. The Boolean model can hence determine whether the cell population is evolving in the desired direction and as such provides valuable feedback for achieving an improved product consistency.
Multi-scale modeling in bone tissue engineering: from biomaterials to intracellular signaling cascades via the cell
Bone tissue engineering (TE) is a promising alternative for the treatment of large bone defects. In the current state of the art scaffolds are seeded with cells and subsequently implanted. Despite some successful studies, bone TE to date still suffers from unpredictable and qualitatively inferior results. To increase both quality and reproducibility, we have to better understand the mechanisms by which bone can be regenerated. Given the increasing evidence that embryonic signaling pathways are recapitulated during tissue regeneration, TE strategies should aim to stimulate those embryonic signaling cascades when developing a tissue construct. As these intracellular signaling networks are complex due to the massive amount of influencing factors (not only other intracellular signals but also e.g. extracellular metabolic signals), mathematical modeling can provide a tool to qualitatively and quantitatively investigate these biological phenomena and design the experimental conditions to optimize both quality and robustness of the tissue construct's production process. This project aims to develop such a multi-scale mathematical model for the study of cell-scaffold interactions by combining a tissue level model that describes the spatio-temporal evolution of the biomaterial, extracellular matrix, blood vessels, cells and growth factors with an intracellular model that describes the activation of relevant signaling cascades.
How do stem cells interact with their extracellular matrix mechanically and what are its mechanobiological implications for skeletal tissue engineering? A computational modelling approach informed by in-vitro experiments
The use of hydrogels enriched with stem cells appears to be a very promising strategy in regenerative medicine. A crucial issue in this approach is how to control stem cell behaviour to achieve a functional tissue. The mechanical signals that cells receive from their microenvironment have been found to be an important regulator of their behaviour. Thereby, it is possible to regulate the behaviour of stem cells utilising a combination of strategies informed by mechanical clues. However, this approach requires quantitative evaluation of the mechanical signals that cells receive from their matrix and relating these signals to their behaviour, i.e. proliferation, differentiation and migration. This study aims to address the role of mechanical signals in regulating tissue patterning (i.e. cartilage and bone formation) in periosteum derived stem cell enriched hydrogels using computational models informed by in-vitro cell culture experiments.
