Cell encapsulation seems to be a promising tool in tissue engineering. However, it has been shown to have several limitations in terms of long-term cell cultures due to an insufficient oxygen supply. In this study we propose the use of novel microcapsules designed for long-term cell culture consisting of an alginate shell and perfluorocarbon (PFC) core, which works as a synthetic oxygen carrier and reservoir. The influence of PFC presence in the culture as well as the size of structures on cell metabolism was evaluated during 21-day cultures in normoxia and hypoxia. We showed significant improvement in cell metabolism in groups where cells were encapsulated in hydrogel structures with a PFC core. The cells maintained a typical metabolism (oxidative phosphorylation) through all 21 days of the culture, overcoming the oxygen supply shortage even in large structures (diameter ¡ 1 mm). Applying PFC in alginate matrices can improve cell metabolism and adaptation in long-term cell cultures.