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Size does matter: an integrative in vivo-in silico approach for the treatment of critical size bone defects.

Carlier A, van Gastel N, Geris L, Carmeliet G, Van Oosterwyck H - PLoS Comput. Biol. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Biomechanics Section, KU Leuven, Leuven, Belgium; Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium; Biomechanics Research Unit, University of Liège, Liège, Belgium.

ABSTRACT
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.

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Predicted tissue fractions at post fracture day (PFD) 90 in bone defects of varying sizes.The 5 mm defect size will be further investigated in the remaining part of this study. The femurs at the right hand side of the figure schematically represent the bone healing outcome at PFD 90, i.e. the formation of a union or a non-union.
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pcbi-1003888-g006: Predicted tissue fractions at post fracture day (PFD) 90 in bone defects of varying sizes.The 5 mm defect size will be further investigated in the remaining part of this study. The femurs at the right hand side of the figure schematically represent the bone healing outcome at PFD 90, i.e. the formation of a union or a non-union.

Mentions: After establishing the in silico and in vivo non-union model, the in silico model was further used to explore the influence of the gap size on the healing outcome (Figure 6). By increasing the gap size, the bone tissue fraction at PFD 90 is reduced whereas the cartilage fraction remains similar (close to zero) and the fibrous tissue fraction is greatly increased (Figure 6). Although the bone tissue fraction reaches 84% in a 3 mm defect, there is no cortical bridging which indicates the formation of a non-union. The simulation therefore predicts that a murine bone defect becomes critical at 3 mm. In the remaining part of this study we will focus on the bone regeneration process in 5 mm defects, in correspondence with the in vivo set-up described above.


Size does matter: an integrative in vivo-in silico approach for the treatment of critical size bone defects.

Carlier A, van Gastel N, Geris L, Carmeliet G, Van Oosterwyck H - PLoS Comput. Biol. (2014)

Predicted tissue fractions at post fracture day (PFD) 90 in bone defects of varying sizes.The 5 mm defect size will be further investigated in the remaining part of this study. The femurs at the right hand side of the figure schematically represent the bone healing outcome at PFD 90, i.e. the formation of a union or a non-union.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222588&req=5

pcbi-1003888-g006: Predicted tissue fractions at post fracture day (PFD) 90 in bone defects of varying sizes.The 5 mm defect size will be further investigated in the remaining part of this study. The femurs at the right hand side of the figure schematically represent the bone healing outcome at PFD 90, i.e. the formation of a union or a non-union.
Mentions: After establishing the in silico and in vivo non-union model, the in silico model was further used to explore the influence of the gap size on the healing outcome (Figure 6). By increasing the gap size, the bone tissue fraction at PFD 90 is reduced whereas the cartilage fraction remains similar (close to zero) and the fibrous tissue fraction is greatly increased (Figure 6). Although the bone tissue fraction reaches 84% in a 3 mm defect, there is no cortical bridging which indicates the formation of a non-union. The simulation therefore predicts that a murine bone defect becomes critical at 3 mm. In the remaining part of this study we will focus on the bone regeneration process in 5 mm defects, in correspondence with the in vivo set-up described above.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Biomechanics Section, KU Leuven, Leuven, Belgium; Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium; Biomechanics Research Unit, University of Liège, Liège, Belgium.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus