The acidic pH-sensitive controlled release of fibroblast growth factor-2 (FGF-2) from a biodegradable hydrogel without any denaturation of the FGF-2 was successfully performed by a combination of FGF-2 activity and acidic pH-sensitivity. We prepared semi-interpenetrating polymer network like hetero-gels (S72-netgels) composed of poly(gamma-glutamic acid) (gamma-PGA) and 72% sulfonated gamma-PGA (gamma-PGA-S72). S72-netgels including 36 mol % sulfonic acid (S72-netgel-36) showed wide acidic pH-sensitive deswelling properties at pH = 2.0-6.0, corresponding to the isoelectric point of carboxylic acid, because of the concentration of protons due to the neighboring sulfonic acids from the carboxylic acids. The S72-netgel-36 (the volume of hydrogel is 7.85 x 10(-2) cm3) can incorporate 280 ng of FGF-2 after 24 h immersion in Tris-HCl buffer (pH = 7.4), including 1.0 microg of FGF-2. The S72-netgel-36 still retained about 60% of the FGF-2 even after 15 days of incubation in fresh Tris-HCl buffer at 37 degrees C because of the stable interaction of FGF-2 with gamma-PGA-S72 in S72-netgel-36. The release of FGF-2 from the S72-netgel-36 was successfully controlled by alternating immersion in pH = 7.4 and acidic pH buffers. Furthermore, the FGF-2 released from the S72-netgel-36 retained its activity without denaturation because the gamma-PGA-S72 in S72-netgel-36 has a protective activity. The acidic pH-sensitive FGF-2 release property of the S72-netgel-36 without denaturation of the FGF-2 may be useful for tissue engineering fields such as neovascular treatment for ischemia and inflammation.