Tiam Mana Saffari

238 CHAPTER 11 bed in this experimental design was not poorly vascularized, questioning the relevance of adding an adipofascial flap. Nevertheless, it seemed that the vascular bundle being in close vicinity and traveling parallel with the nerve over an adequate distance in the adipofascial bed was a contributing factor to revascularization 20,21 . In contrast, the revascularization of nerve allografts that were not wrapped in a vascularized adipofascial flap remained poor. The second finding suggests that an improved vascularized bed promotes longitudinal inosculation, in particular proximal inosculation, and confirms the theory of centripetal revascularization. There has been controversy regarding the mechanism of revascularization and studies have investigated this topic using various approaches to assess angiogenesis including histology 22,23 , angiography 19,24,25 and evaluation of blood flow 5,18,26-28 . While previous studies support bidirectional longitudinal inosculation from the proximal and distal ends of the nerve graft 17-19,24 , a more recent study by Chalfoun and colleagues is in line with our findings and also favored proximal vascular inosculation 26 . Advanced technology, such as micro CT, used in this study, provides the ability to identify 3D interconnectivity of the vasculature and may be used to describe spatial differences in revascularization in more detail 29 . What effect does angiogenesis have on nerve allografts at a cellular level? Theoretically, a well vascularized bed enhances the local cellular environment near the nerve repair site -the paracrine environment- to support tissue healing after injury and subsequently diminish fibrosis 30 . The hallmark of fibrosis is the chronic accumulation of myofibroblasts, which are the primary extracellular matrix (ECM)-secreting cells. Depending on the ECM composition, this could lead to either physiological or pathological tissue repair 31 . Myofibroblasts in fibrotic diseases originate from several sources, including from phenotypic differentiation of fibrocytes and transition of endothelial cells, often regulated by transforming growth factor (TGF)-β 32,33 . While chronic hypoxia stimulates this differentiation, it has been suggested that acute hypoxia induces angiogenesis which subsequently decreases the conversion of fibroblasts into pro-fibrotic myofibroblasts 34,35 (Figure 1). Furthermore, angiogenesis is critical for ECM synthesis that is needed for remodeling successful tissue repair 36,37 .