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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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Influence of the muscle as a source for vascularization, MSCs, growth factors or a combination thereof on the bone regeneration process.The tissue fractions are measured at post fracture day (PFD) 90. The standard condition is indicated in bold and has the following dimensionalized parameter values for the initial conditions in the central area of the fracture callus: cm,init = 2.103 cells/ml, gbc,init = 10 ng/ml, cf,init = 1.104 cells/ml, mf,init = 0.01 g/ml, ninit = 3.7%. Table S2 summarizes the tissue fractions quantitatively.
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pcbi-1003888-g008: Influence of the muscle as a source for vascularization, MSCs, growth factors or a combination thereof on the bone regeneration process.The tissue fractions are measured at post fracture day (PFD) 90. The standard condition is indicated in bold and has the following dimensionalized parameter values for the initial conditions in the central area of the fracture callus: cm,init = 2.103 cells/ml, gbc,init = 10 ng/ml, cf,init = 1.104 cells/ml, mf,init = 0.01 g/ml, ninit = 3.7%. Table S2 summarizes the tissue fractions quantitatively.

Mentions: In order to further unravel the potential mechanisms of interaction that exist between the bone regeneration process and the overlying skeletal muscle, the role of the skeletal muscle as a source for vascularization, progenitor cells and growth factors or a combination thereof was investigated by applying different boundary conditions to the in silico model (Figure 7–8). More specifically, the contribution of the muscle to the vascularization of the fracture callus was simulated by initializing additional endothelial cells on the border of the central callus area with the muscle, either partially or fully covering the fracture gap. The influence of the muscle as a source of MSCs or growth factors was represented by a Dirichlet boundary condition, applied to the upper border for the entire duration of the simulation (i.e. 90 days) and fully covering the fracture gap (Figure 7). The value of the Dirichlet boundary conditions is equal to the ones applied in the standard case, i.e. 2.104 cells/ml for the MSCs and 2 µg/ml for the osteochondrogenic growth factors [25], [38]–[40]. Since the mathematical model does not take into account any mechanoregulatory stimuli, the influence of mechanoregulatory stimuli generated by the overlying muscle on the bone formation processes cannot be evaluated in this study.


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)

Influence of the muscle as a source for vascularization, MSCs, growth factors or a combination thereof on the bone regeneration process.The tissue fractions are measured at post fracture day (PFD) 90. The standard condition is indicated in bold and has the following dimensionalized parameter values for the initial conditions in the central area of the fracture callus: cm,init = 2.103 cells/ml, gbc,init = 10 ng/ml, cf,init = 1.104 cells/ml, mf,init = 0.01 g/ml, ninit = 3.7%. Table S2 summarizes the tissue fractions quantitatively.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003888-g008: Influence of the muscle as a source for vascularization, MSCs, growth factors or a combination thereof on the bone regeneration process.The tissue fractions are measured at post fracture day (PFD) 90. The standard condition is indicated in bold and has the following dimensionalized parameter values for the initial conditions in the central area of the fracture callus: cm,init = 2.103 cells/ml, gbc,init = 10 ng/ml, cf,init = 1.104 cells/ml, mf,init = 0.01 g/ml, ninit = 3.7%. Table S2 summarizes the tissue fractions quantitatively.
Mentions: In order to further unravel the potential mechanisms of interaction that exist between the bone regeneration process and the overlying skeletal muscle, the role of the skeletal muscle as a source for vascularization, progenitor cells and growth factors or a combination thereof was investigated by applying different boundary conditions to the in silico model (Figure 7–8). More specifically, the contribution of the muscle to the vascularization of the fracture callus was simulated by initializing additional endothelial cells on the border of the central callus area with the muscle, either partially or fully covering the fracture gap. The influence of the muscle as a source of MSCs or growth factors was represented by a Dirichlet boundary condition, applied to the upper border for the entire duration of the simulation (i.e. 90 days) and fully covering the fracture gap (Figure 7). The value of the Dirichlet boundary conditions is equal to the ones applied in the standard case, i.e. 2.104 cells/ml for the MSCs and 2 µg/ml for the osteochondrogenic growth factors [25], [38]–[40]. Since the mathematical model does not take into account any mechanoregulatory stimuli, the influence of mechanoregulatory stimuli generated by the overlying muscle on the bone formation processes cannot be evaluated in this study.

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