The insulin-transport enhancing effects of a pH-sensitive poly((methacrylic acid)-grafted-poly(ethylene glycol)) hydrogel system were studied using Caco-2 monolayers as an in vitro model of intestinal transport. Further, the ability of the hydrogel system to protect entrapped proteins through the upper gastrointestinal tract via digestion in simulated gastric and simulated intestinal fluids with digestive enzymes was confirmed. Caco-2 cell monolayers were exposed to a series of formulations including insulin alone, the polymer in insulin solution, insulin-loaded polymer (ILP) and ILP previously subjected to simulated digestive fluids with enzymes. These studies demonstrated greatly increased insulin transport for the ILP samples when compared with insulin alone and insulin in the presence of polymer, P(app)=12.7 x 10(-8) cm/s and 6.61 x 10(-8) cm/s versus 0.07 x 10(-8) cm/s and 0.06 x 10(-8) cm/s, respectively. While enhanced transport with the ILP was observed, the largest changes in TEER values did not coincide with the highest amounts of insulin transport, this suggests that the paracellular route may not be the sole mechanism of transport. Further, as the Caco-2 cell line has been demonstrated to possess the insulin receptor, active transport or a mixed mechanism cannot be ruled out.