Mechanobiology of Bone - Engineered Bone: Tissue Engineering Intelligence Unit - page 31

Figure 3. Schematic representation of tissue development in distraction osteogenesis (DOG). After os-
teotomy the bone is stabilized. In this latency period, a fracture callus forms. During distraction, the callus
amplifies, while ossification starts around the cortical edges and progresses in the direction of the applied
strain. At the end of distraction, the bone is stabilized again and the osteotomy gap is bridged by bone.
Hereafter, full consolidation of the gap takes place. The composition of the callus tissue varies between
fibrous connective tissue and fibrocartilage.
itself. During clotting, various factors are released, such as platelet derived growth factor (PDGF)
and transforming growth factor-beta (TGF- β ). Thereafter, inflammatory cells invade the wound
rapidly. They also secrete factors e.g., fibroblast growth factor (FGF) as well as PDGF and
TGF- β . 27 In addition, they are thought to produce cytokines including interleukin-1 (IL-1)
and interleukin-6 (IL-6). 28 Growth factors released by bone include bone morphogenetic pro-
teins (BMPs), TGF- β , PDGF, insulin-like growth factors I and II (IGF-I, IGF-II) and FGFs. 27
Hence, within the first couple of hours after osteotomy or fracture a multi-factorial environ-
ment is created. This complex biochemical milieu is thought to be responsible for the invasion,
proliferation and differentiation of cells in the wound. Interestingly, the majority of these fac-
tors play distinct roles in the ontogenesis of the embryonic skeleton. 28 The coordinated regula-
tion of successive events by these factors is still poorly understood. It is clear, however, that
once connective tissue is formed, its further development depends to a large extent on the
mechanical context.
Bone repair can follow various pathways with various combinations of bone formation via
direct, endochondral or intramembranous ossification. In fracture healing these pathways are
modulated by the stiffness of the fixation. 29 When the fracture is fixed rigidly, direct bone
formation, without the formation of a callus can occur. Apparently, a stable environment with
relatively low strains stimulates the direct differentiation towards bone forming osteoblasts.
Under less rigid fixation bone healing occurs by endochondral ossification. Interfragmentary
movement stimulates the growth of callus tissue, but it inhibits the conversion of soft connec-
tive tissue into bone. 29-32 In contrast, pure axial loading of the callus and load bearing seem to
stimulate the formation of bone. 33,34
In DOG the applied strain and frequency affect the pathway and the success of bone devel-
opment. 35,36 If the distraction is too slow, bone formation will catch up with the formation of
new connective tissue. Consolidation will happen too soon and further distraction is impos-
sible. Too large distraction rates (i.e., large strain values) lead to disorganized fibrous tissue
formation without the formation of bone, resulting in nonunion. 35,37 Within this window,
distraction is usually successful. The course of tissue development is modulated by the distrac-
tion magnitude and rate. 37-39 For instance, Meyer et al 40 showed that low strains of 0.2% lead
to intramembranous bone formation, with active osteoblasts in the whole distraction gap and
no clear anisotropy. Strains of 2% gave highly oriented collagen fibrous tissue, with bone for-
mation at the borders of the gap in the form of trabeculae growing in the direction of tension.
Furthermore, high strains of 20% or 30% result in loosely arranged collagen, tissue failure, and
lack of mineralization.