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Introduction 4 et. al.

Introduction 4 et. al. 22 ). Despite this promising outcome in several animal studies, TE until now does not provide a treatment alternative for large bone defects, since it’s still unclear which dynamic interaction of cells, cytokines and matrices provokes the natural bone healing process. Therefore an insight into bone development, bone mechanics and into biological aspects is necessary. 1.2. Bone biology 1.2.1. Bone development There are two fundamentally different ways of ossification. Firstly, direct ossification of embryonic connective tissue (intramembranous ossification) and secondly the replacement of hyaline cartilage by compact bone (endochondral ossification). Endochondral ossified bones, mainly large hollow bones such as femur, tibia or humerus, represent most of the adult bones. Fewer bones, such as clavicula or the skull develop by intramembranous ossification 23 . Both types of bone arise during embryonic development by a complex interaction of diffusion, oxygen gradients and cellular apoptosis. The sclerotom plays a pivotal role during early embryonic development of bone, cartilage and ligaments. The initial cartilaginous vertebral body system ossifies towards the final skeletal body system within the twelfth week of development and usually ends between the 23th to 25th year of age. The growth of the upper and lower extremities occur through the limb buds (fifth week of development) – excrescences of the lateral abdominal walls, mesenchymal tissue which is covered with ectoderm 24 . Within the sixth week of development a programmed cell death (apoptose) emerges at the distal point of the limb and ends up in the development of the hands or feet, respectively. Partial oxygen concentration within the uterus attached great importance to embryonic development. In the beginning of the 90s, Fischer and Bavistor reported a low oxygen level for the first embryonic stages within the uterus for several vertebrate species 25 and despite the global biological mechanism during bone development is inadequately understood, a primary developmental motor are tissue oxygen gradi-

Introduction 5 ents 26 . To guarantee a sufficient nutrient and oxygen supply for fast adenosine triphosphate (ATP) synthetisation within hypoxic and hypertrophic cartilage, chondrocytes release the vascular endothelial growth factor (VEGF). This proangiogenic signal molecule, stimulates the proliferation and migration of surrounding endothelial cells and has various cofactors like transforming growth factor-β (TGF-β), bone morphogenetic protein (BMP) or insulin-like growth factor 1 (IGF-1) 27,28 . All these proinflammatory cytokines, growth factors and mechanical stimuli are closely related to the key transcription factor in hypoxic environment. The hypoxia-inducible factors (HIF) are α-β-heterodimers which mediate the cellular adaption to changing oxygen levels. Up to now three α and one β heterodimers are known (HIF-1α, HIF-2α, HIF- 3α, and HIF-1β). Under cellular hypoxia, HIF-α incorporates the nucleus and dimerizes to the HIF-1β subunit. The activated dimer binds to promoters of hypoxiaresponsive genes, which affect cell proliferation, metabolism or cell maturation 29-32 . 1.2.2. Bone anatomy on a macro- and nanostructual level Bone is one of the most intriguingly progresses during evolution of endoskeletal species. The highly hierarchical structure, beginning with the macroscopic appearance over spongy/compact bone, osteons/Haversian canals, fibril arrays and mineralized crystals finally ends up in tropocollagen 23,33 . The most prominent proteins within the complex bone are collagens, as well as additional components like fibronectin, laminin, osteocalcin, proteoglycans and osteonectin. This fraction of so called noncollagenous proteins (NCPs) accounts just up to 10% of the bones wet weight 34 . The mineralised part consists of hydroxyapatite [Ca10(PO4)6(OH)2], bruschite [CaHPO4(H2O)2] and octocalciumphosphate [Ca8H2(PO4)6(H2O)5]. Additionally, the availability of Ca 2+ and PO4 3- is essential for the continuous tissue turnover. This great variety of substructures, material composition and physiological elements makes a detailed breakdown necessary. Figure 2 shows an illustration of the bone hierarchy.

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