Background: The design of new technologies for treatment of human disorders such as protein deficiencies is a complex and difficult task. Particularly, the construction of artificial organs, based on the immunoisolation of protein-secreting cells, requires the use of suitable materials which have to be biocompatible with the immunoisolated cells and avoid any inappropriate host response. Methodology/Principal Findings: This work investigates the in vivo behavior of mechanically resistant hybrid beads which can be considered as a model for artificial organ for cell therapy. This hybrid system was designed and fabricated via the encapsulation of living cells (HepG2) within alginate-silica composites. Two types of beads (alginate-silica hybrid (AS) or alginate/silica hybrid subsequently covered by an external layer of pure alginate (ASA)), with or without HepG2 cells, were implanted into several female Wistar rats. After four weeks, the potential inflammatory local response that might be due to the presence of materials was studied by histochemistry. The results showed that the performance of ASA beads was quite promising compared to AS beads, where less abnormal rat behaviour and less inflammatory cells in histological sections were observed in the case of ASA beads. Conclusions/Significance: The current study highlights that alginate-silica composite materials coated with an extra-alginate shell offer much promise in the development of robust implantation devices and artificial organs.