Characterization of glucose-sensitive insulin release systems in simulatedin vivo conditions

We studied the glucose-responsive insulin controlled release system based o n the hydrogel poly(2-hydroxyethyl methacrylate-co-N,N-dimethylaminoethyl m ethacrylate), also called poly(HEMA-co-DMAEMA), with entrapped glucose oxid ase, catalase and insulin. When exposed to physiological fluids, glucose di ffuses into the hydrogel, glucose oxidase catalyzes the glucose conversion to gluconic acid, causing swelling of the pH-sensitive hydrogel and subsequ ently increased insulin release. The higher the glucose concentration in th e medium, the higher and faster the swelling and release rates. The effects of polymer morphology and oxygen availability on hydrogel swelling and on insulin release kinetics were tested. Polymer morphology was modified by ch anging the crosslinking agent (tetraethylene glycol dimethacrylate) concent ration (0-0.95 vol%). Oxygen availability was modified by changing the immo bilized catalase concentration (0-15 units catalase per unit glucose oxidas e) and by bubbling oxygen through the medium. The results indicated that: ( i) Hydrogels without crosslinking agent were found to be stable in water, a nd their sensitivity to pH and glucose was higher than the chemically cross linked hydrogels. (ii) Immobilization of catalase in addition to glucose ox idase in hydrogels prepared without crosslinking agent, resulted in enhance d swelling kinetic. In addition, we carried out primary in vivo experiments on rats, which demonstrated that at least some of the entrapped insulin re tains its active form and is effective in reducing blood glucose levels. Mo reover, no tissue encapsulation was observed around matrices implanted in t he peritoneum. In conclusion, the pi-I-sensitive hydrogel poly(HEMA-co-DMAE MA) can be manipulated to produce glucose-responsive insulin release system that is effective in reducing blood glucose levels. (C) 2000 Elsevier Scie nce Ltd. All rights reserved.