Molecular and cellular mechanisms of collagen degradation in the foreign body reaction

The biopolymer collagen is often used as a scaffolding biomaterial in tissue engineering. Like any other biomaterials, the implantation of collagen scaffolds induces a local inflammatory reaction known as a foreign body reaction (FBR). The FBR to collagen scaffolds involves a complex cascade of spatiotemporally regulated and interconnected processes that include cellular infiltration, activation of inflammatory cells, phagocytosis and proteolysis, which ultimately result in the resolution and degradation of the implanted scaffold. Ideally, the degradation rate should match the speed of tissue regeneration. The aim of this thesis was to discover the molecular and cellular mechanisms of degradation of collagen scaffolds in the FBR, which are largely unknown. Our data have provided several striking findings regarding the nature and regulation of the enzymatic degradation and phagocytosis of collagen scaffolds. IL-10, IL-13, TIMP-1 and DDR-2 have been identified as potential therapeutic factors in the regulation of MMP-based proteolysis in the extracellular enzymatic degradation of collagen. IFN-γ appears to be the optimal activator for the phagocytosis of collagen by macrophages via the up-regulation of MMP-14 and Endo180. This effect can be neutralised by the addition of IL-10. Moreover, our data have also showed that it is extremely important to choose an appropriate substrate and design the physical and chemical nature of the scaffold so that its degradation can be tuned to the rate of tissue regeneration. Although our data have expanded our understanding of the regulation of collagen degradation, it is still a long way from bench to bed.