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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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Related in: MedlinePlus

Predicted amount of bone formation at PFD 90 in a large defect surrounded by a compromised environment as a function of the PFD at which the treatment was initiated.The treatment consists of a single injection of cells (cm = 1.106 cells/ml), growth factors (gbc = 1.103 ng/ml) or a combination thereof. The results of injections at PFD 0 can also be found in Table S1.
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pcbi-1003888-g013: Predicted amount of bone formation at PFD 90 in a large defect surrounded by a compromised environment as a function of the PFD at which the treatment was initiated.The treatment consists of a single injection of cells (cm = 1.106 cells/ml), growth factors (gbc = 1.103 ng/ml) or a combination thereof. The results of injections at PFD 0 can also be found in Table S1.

Mentions: Finally, we used the in silico model to optimize the treatment strategy of the previous section for critical size defects surrounded by a compromised host environment. As can be concluded from Table S1, the lack of muscular contribution to the vascularization of the fracture callus as well as of osteoprogenitor cells or growth factors, greatly hampers the bone regeneration process and results in the formation of a non-union. Furthermore, the initial conditions can be tuned to improve the amount of bone formation but are insufficient to provide complete healing of the critical size defect (Table S1). This was attributed to the delayed vascularization of the central callus area, leading to hypoxia and cell death. In order to improve the limited biological potential of the fracture callus and host environment, additional progenitor cells or growth factors can be injected in the fracture callus. However, cellular strategies would miss their therapeutic target if injections would take place at day 0, since cell survival would be very limited in these challenging hypoxic conditions. Therefore, we investigated whether a single injection of MSCs, osteochondrogenic growth factors or a combination thereof at a later time point would improve the bone healing outcome, as in this way the blood vessel network will have restored at least partially (Figure 13).


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 amount of bone formation at PFD 90 in a large defect surrounded by a compromised environment as a function of the PFD at which the treatment was initiated.The treatment consists of a single injection of cells (cm = 1.106 cells/ml), growth factors (gbc = 1.103 ng/ml) or a combination thereof. The results of injections at PFD 0 can also be found in Table S1.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003888-g013: Predicted amount of bone formation at PFD 90 in a large defect surrounded by a compromised environment as a function of the PFD at which the treatment was initiated.The treatment consists of a single injection of cells (cm = 1.106 cells/ml), growth factors (gbc = 1.103 ng/ml) or a combination thereof. The results of injections at PFD 0 can also be found in Table S1.
Mentions: Finally, we used the in silico model to optimize the treatment strategy of the previous section for critical size defects surrounded by a compromised host environment. As can be concluded from Table S1, the lack of muscular contribution to the vascularization of the fracture callus as well as of osteoprogenitor cells or growth factors, greatly hampers the bone regeneration process and results in the formation of a non-union. Furthermore, the initial conditions can be tuned to improve the amount of bone formation but are insufficient to provide complete healing of the critical size defect (Table S1). This was attributed to the delayed vascularization of the central callus area, leading to hypoxia and cell death. In order to improve the limited biological potential of the fracture callus and host environment, additional progenitor cells or growth factors can be injected in the fracture callus. However, cellular strategies would miss their therapeutic target if injections would take place at day 0, since cell survival would be very limited in these challenging hypoxic conditions. Therefore, we investigated whether a single injection of MSCs, osteochondrogenic growth factors or a combination thereof at a later time point would improve the bone healing outcome, as in this way the blood vessel network will have restored at least partially (Figure 13).

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