Last modified: 2014-06-09
Abstract
Introduction
The healing of a bone fracture strongly depends on the development of a new blood vessel network
(angiogenesis) in the fracture zone. In a previous study, a multiscale model of sprouting angiogenesis
during fracture healing, including Dll4-Notch1 signalling to determine tip cell selection (MOSAIC [1]),
was extended with a rigorous description of the influence of oxygen on several cellular processes.
Currently, we are using this mathematical model as a tool for a more in depth investigation of the
influence of oxygen in critical size defects and possible therapies thereof.
Results and Discussion
The oxygen model correctly simulated the
formation of a non-union in critical size
defects and was used to study the underlying
mechanisms. In the central region of the
fracture callus, we found that all cells die due
to severe hypoxia, leading to bone healing
arrest. This finding prompted us to explore
the influence of the vasculature from the host
environment on the fracture healing outcome.
Experimental evidence has previously shown
that blood vessels originating in the overlying
muscle contribute to the revascularization of
the fracture callus [2]. Interestingly, the
oxygen model predicts a considerably
improved healing outcome in the case of full
muscle contribution and an intermediate
result if the fracture callus is only partially
supplied with blood vessels from the host
environment (Fig 1).
Figure 1: (A) The geometrical domain
considers one-fourth of the real fracture callus
geometry of a critical size defect (assuming
symmetry); 1 periosteal callus; 2 intercortical
callus; 3 endosteal callus; 4 cortical bone ends.
(B) Predicted spatiotemporal evolution of the
active vasculature and bone matrix density (x
0.1 g/ml) in a critical size defect with different
contributions of the overlying muscle to the
vascularization of the fracture callus. Red dots
at day zero represent endothelial cells from the
host environment.
Motivated by these results, we investigated whether the injection of either mesenchymal stem cells
(MSCs), osteochondrogenic growth factors or the combination thereof in an impaired environment, i.e.
without muscle contribution, must be delayed in order to allow a (partial) restoration of the vasculature
and be more effective (Fig 2). We found that the injection of only growth factors at either post fracture
day (PFD) 7, 14, 28, 42 or 56 does not improve the bone formation since oxygen tensions still become
critically low in the central callus area due to delayed revascularization. The injection of MSCs is more
beneficial at PFD 42 or 56 since the vasculature in the interfragmentary gap is already partially restored,
sustaining the viability of the injected cells. Similar conclusions can be drawn for the combination
product, except that the combination yields better results at PFD 56 than the injection of cells alone (Fig
2).
Figure 2: Predicted amount of bone formed at PFD
90 as a function of the PFD at which the treatment,
consisting of a single injection of cells, growth factors
or a combination thereof, was initiated.
Conclusions
This work clearly indicates the importance of angiogenesis in tissue engineering. Future work will focus
on the in silico design of efficient vascularization strategies for tissue engineering constructs, including
angiogenic growth factor delivery and in vitro prevascularization or a combination thereof.
References
1. Carlier A., et al. PLoS Comput Biol, 8(10), 2012. 2. Harry L., et al. Plast Reconstr Surg, 124, 2009
Acknowledgments
Aurélie Carlier is a PhD fellow of the Research Foundation Flanders (FWO-Vlaanderen).
Short abstract
In this study we hypothesized that the spatiotemporal distribution of oxygen tension, influenced by
amongst others cellular consumption as well as the timely revascularization of the callus is an important
determinant of the occurrence of fracture non-unions. Therefore, we performed a thorough sensitivity
analysis on a previously established multiscale bioregulatory model of fracture healing in order to unravel
the non-intuitive oxygen dynamics. In a next step this knowledge was used to design potential treatment
strategies.
Purpose
The main objective of this study was to use a multiscale model of fracture healing to explore the
underlying mechanisms of the occurrence of fracture non-unions and design potential treatment strategies
thereof.
Keywords
Multiscale – bone fracture healing – hybrid – model