Islet encapsulation has the potential to enable transplantation without requirement for life-long immunosuppression. The period between implantation and revascularisation is most harmful for encapsulated islets as they receive nutrients and oxygen exclusively via diffusion. This critical time gap must be bridged with a temporary oxygen supply to prevent inflammation and apoptosis. Hence, we compared the efficiency of individual components of an oxygen-delivering matrix (hyaluronic acid (HA); HA + perfluorodecalin nanoemulsion; HA + perfluorodecalin nanoemulsion + oxygen) to provide a substitute for the extracellular matrix and to facilitate human islet survival. The islets were loaded into silicone-based macroencapsulation devices with multi-scale porous membranes designed to optimise revascularisation. Four to five days of normoxic culture revealed that non-oxygen-charged nanoemulsion prevented islet disintegration but did not reduce necrosis or apoptosis. Oxygen supply decreased the generation of reactive oxygen species and chemokines, thereby increasing islet yield. Stimulated insulin secretion of encapsulated islets was marginal and severely delayed. Islets incubated in oxygen-precharged nanoemulsion were characterised by the highest stimulation index. These data suggest that islet survival in macroencapsulation devices can be optimised with a multi-functional matrix providing mechanical support and temporary oxygen supply to reduce the production of pro-inflammatory mediators. Suitable oxygen delivery systems with an extended life span must identified before in vivo experiments can be undertaken.