The reestablishment of an adequate

The reestablishment of an adequate blood vessel system is of utmost
importance for the success of bone healing. Long-standing preclinical
and clinical evidence has established a strong correlation between the
impairment of vascular function and failure of fracture healing (delayed
union or non-union) [70].
Bone tissue engineering represents an appealing strategy to improve
non-healing osseous defects. Reconstruction of damaged bone using
this technique relies on the combination of a biocompatible scaffold,
osteogenic cells and osteogenic or angiogenic growth factors.
Furthermore, mechanical stabilization of the defect and an adequate
host response are critical to ensure successful bone formation [71,
72]. Despite the clear potential of engineered constructs, translation
into the clinic remains difficult. One of the major limitations of this
approach is the inability to provide sufficient blood vessel supply
during the early stages of bone regeneration, reflected by the limited
survival of the osteogenic cells early after implantation [73,74]. Upon
implantation of the construct, an angiogenic response is elicited by
inflammatory cytokines as part of the normal healing process [75].
Neovascularization of the scaffold will occur by invading blood vessels
deriving from the surrounding host vasculature. However, the slow rate
of invasion of blood vessels into the scaffold (b1 mm per day) [76]
makes it an insufficient process to timely vascularize tissues of clinically
relevant size.
To overcome this problem, several methods have been proposed
to improve the vascularization of bone constructs in experimental
models: the delivery of angiogenic growth factors, the use of EC to
engineer a vascular network or a hybrid approach that combines
microsurgery approaches with bone tissue engineering concepts
[75] (Fig. 4).