A new approach combining electrostatic and covalent bonds was established for the formation of resistant capsules with long-term stability under physiol. conditions. Three kinds of interactions were generated in the same membrane: (1) electrostatic bonds between alginate and poly-L-lysine (PLL), (2) covalent bonds (amides) between propylene-glycol-alginate (PGA) and PLL, and (3) covalent bonds (amides) between BSA and PGA. Down-scaling of the capsules size (?1 mm diam.) with a jet break-up technol. was achieved by modifying the rheol. properties of the polymer soln. Viscosity of the PGA soln. was reduced by 95% with four successive pH stabilizations (pH 7), while filtration (0.2 mm) and sterilization was possible. Covalent bond formation was initiated by addn. of NaOH (pH 11) using a transacylation reaction. Kinetics of the chem. reaction (pH 11) were simulated by two math. models and adapted in order to preserve immobilization of animal cells. It was demonstrated that diffusion of NaOH in the absence of BSA resulted in gelation of 94% of the bead and death of 94% of the cells after 10 s reaction. By addn. of BSA only 46% of the cells were killed within the same reaction time (10 s). Mech. resistance of this new type of capsule could be increased 5-fold over the std. polyelectrolytic system (PLL-alginate). Encapsulated CHO cells were successfully cultivated for 1 mo in a repetitive batch mode, with the mech. resistance of the capsules decreasing by only 10% during this period. The combination of a synthetic and natural protein resulted in enhanced stability toward culture medium and proteolytic enzymes (250%). [on SciFinder (R)]