Since the introduction of CHEMFETs much attention has been paid to the development of multi-ion sensors especially for extra-corporeal continuous patient monitoring. Most of the systems use different ionophores, suspended in inert matrices on top of the gate insulator, to provide multi-ion sensitivity. A system is developed whereby glass is used to encapsulate the individual sensors thereby providing not only an excellent encapsulation but also a means to immobilize hydrogels and membranes. To avoid the problem of the reference electrode a pH-sensitive ISFET with a retarded pH response was developed, thereby creating the possibility to operate this ISFET as an ion-insensitive FET over short periods of time (pseudo-REFET). A multi-ion sensor, consisting of a pH-sensitive, a potassium-sensitive and a calcium-sensitive ISFET together with a pseudo-REFET, is developed. It is shown that in the differential measurement set-up, the system exhibits a high precision in combination with a high sample frequency. Furthermore the modelization of the pseudo-REFET permits the estimation of diffusion coefficient of hydrogen ions in different hydrogels.