Use this URL to cite or link to this record in EThOS:
Title: Hypoxia-mimicking bioactive materials for skeletal tissue engineering
Author: Azevedo, Maria Manuel Goncalves
ISNI:       0000 0004 2706 1786
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
Availability of Full Text:
Access from EThOS:
Access from Institution:
The next generation of regenerative medicine solutions will depend on smart materials that can activate “self-healing” mechanisms. Cells respond to changes in pO2 through a hypoxia-sensing pathway, the HIF-1 pathway, which activates numerous processes necessary for bone and cartilage development and for normal tissue repair. Control of these processes is critical in tissue engineering (TE), therefore this thesis aimed to develop novel hypoxia-mimicking materials for skeletal TE. Resorbable bioactive glasses (BG) were chosen as the delivery system for a hypoxia-stimulating ion, Co2+. Two series of melt-derived BGs containing increasing amounts of Co2+ were synthesised. Co2+ was equally distributed through both the silicate and orthophosphate phases of the BG, and acted as both an intermediate oxide and network modifier in the silicate network. Co2+ significantly decreased the ion-release rate and HCA-forming ability of BG, and a controlled release of Co2+ was achieved. The biological activity of the hypoxia-mimicking BGs on human mesenchymal stromal cells (hMSCs) and endothelial cells (ECs) was assessed. In both cell types the Co2+-containing BGs activated the HIF-1 pathway. hMSCs exposed to the BG reduced their proliferation rate but enhanced glycolytic activity and collagen production, and VEGF expression was up-regulated in a concentration-dependent manner. Exposure of ECs to the hypoxia-mimicking BGs reduced cell viability. However, in a co-culture system with hMSCs, EC viability and angiogenic potential were rescued. These results suggest that the hypoxia-mimicking BGs can activate several processes involved in skeletal regeneration, including cell differentiation, ECM production and angiogenesis, either by a direct effect on hMSCs or by a paracrine effect of hMSCs. Finally, the hypoxia-mimicking BGs were successfully incorporated into collagen freeze-dried scaffolds. hMSC viability was not affected by the presence of the Co2+-containing BG. Importantly, the BG was still able to activate the HIF-1 pathway when incorporated into collagen scaffolds. The results presented in this thesis strongly suggest the potential of the hypoxia-mimicking BGs for skeletal TE.
Supervisor: Stevens, Molly Sponsor: Fundação da Ciência e Tecnologia
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral