ARUP; ISBN: 978-0-9562121-5-3 - CMBBE 2012 - Cardiff University

4. RESULTS AND DISCUSSION
The MOSAIC model predicts the evolution of the continuous variables as well as the
evolution of the intracellular variables during normal fracture healing. Fig. 2 compares
the predictions of the Peiffer-model [9] and the MOSAIC model with the
experimentally measured tissue fractions of Harrison et al. in a rodent standardized
fracture model [11]. Both models capture the general trends in the experimental data:
the bone tissue fraction gradually increases throughout the healing process; the fibrous
tissue fraction disappears; the cartilage template is first produced and later replaced by
bone. After one, two and three weeks the surface fraction of the blood vessels in the
callus is respectively 3.05%, 35.54% and 65.86%.
Fig. 2. In silico and in vivo evolution of normal fracture healing. Temporal evolution of the bone,
cartilage and fibrous tissue fractions (%) in the periosteal, intercortical and endosteal callus as predicted
using the hybrid model of Peiffer et al. [9] and the newly developed multiscale model (MOSAIC) and as
measured by Harrison et al. [11].
Fig. 3 shows that the tip cells have high VEGFR-2 levels. The stalk cells are inhibited
and have low VEGFR-2 and actin levels. Remark that the Dll4-Notch signaling stops
when the VEGF-concentration in the callus drops (the VEGFR-2 levels stay constant).
The VEGF concentration goes down since the vasculature brings enough oxygen to the
fracture site. The endothelial cells far away from the vascular front all have maximal
VEGFR-2 levels. The heterozygous knockout genotypes (Fig. 3. left) show an increased
sprouting due to a clearly reduced inhibition of the tip cell phenotype. The
overexpression of Dll4 (Fig. 3. right) increases the inhibition of the tip cell phenotype
resulting in a decrease of the vascular density. These results are consistent with the
experimental observations [4, 12, 13]. Hellström et al. [4] convincingly showed that the
heterozygous inactivation of the Notch ligand Dll4 promotes an increase in the number
of tip cells in the retina of newborn mice.