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The cellular response to hypoxia is vital for skeletal tissue development and regeneration. Numerous processes, including progenitor cell recruitment, proliferation and differentiation, are activated through the hypoxia pathway in a low oxygen pressure environment. Novel materials-based strategies designed to activate the hypoxia pathway are therefore of great interest for orthopaedic tissue engineering.Here resorbable bioactive glasses (BG) were designed to activate the hypoxia pathway by substitution of Co 2+ for Ca 2+ in the BG and substitution of Co 2+ and Ca 2+ /+2Na + for Si 4+ . This allowed for the controlled release of cobalt, whilst controlling BG bioactivity (apatite-forming ability). Two series of soda-lime-phosphosilicate glasses were manufactured with increasing concentrations of cobalt. Compositions were calculated to maintain constant network connectivity (2.13) by considering cobalt as an intermediate oxide in the first series, and as a network modifier in the second series. Mg 2+ and Zn 2+ were added to one of the Co 2+ -containing glasses to inhibit HCA formation since delay or inhibition of HCA formation is essential for the use of BG in soft tissues, as is the case of cartilage.Cobalt was present in both the silicate and phosphate phases of the BG. In addition, evidence was found for it playing a dual role in the silicate phase, acting as both an intermediate oxide and taking part in the network as well as being a network modifying oxide. Consistent with an intermediate oxide role, the presence of cobalt in the BG was shown to decrease ion release. HCA formation was delayed with cobalt additions. Mg 2+ and Zn 2+ further delayed HCA formation.Cobalt release was found to be proportional to cobalt content of the BGs enabling the controlled delivery of cobalt in therapeutic active doses.