Novel Hydrogels for Rhythmic Pulsatile Drug Delivery Siddharthya K. Mujumdar, 1 Amardeep S. Bhalla, 2 Ronald. A Siegel 1,2 Summary: We are investigating an autonomous glucose-driven hydrogel/enzyme- based device prototype for rhythmic, pulsed delivery of gonadotropin releasing hormone (GnRH). The device employs a pH-sensitive hydrogel membrane in con- junction with the enzyme glucose oxidase. This system delivers GnRH in rhythmic pulses when exposed to a constant level of glucose. These pulses result from autonomous pH oscillations inside the device that are created by an unstable nonlinear feedback between hydrogel permeability to glucose and production of acid by glucose oxidase. Previous versions of this prototype utilized p(N-isopropylacrylamide-co-methylacrylic acid) p(NIPA-co-MAA) hydrogels, with 10 mol% MAA incorporated. With this membrane, which undergoes a volume transition (VT) near pH 5, pH oscillations centered around pH 5 are observed. This range is too low to sustain oscillations in physiologically buffered media. To shift the operating pH of oscillations closer to physiologic pH, we have sought ways to increase the pH of the volume transition. In this study we show that increasing the side chain length of the a-alkylacrylic acid (RAA) comonomer enhances the overall hydrophobicity of the copolymer, and shifts the VT pH closer to physiological pH values. We also demonstrate the ability of such membranes to affect an alkaline shift in the range of oscillations in the prototype oscillator device. Keywords: hydrogels; hydrophobic; pH-sensitive; N-isopropylacrylamide; pulsatile Introduction Poly(N-isopropylacrylamide) [p(NIPA)] hydro- gels exhibit a sharp volume transition (VT) in response to infinitesimal changes in temperature. [1–4] NIPA can be copolymer- ized with other comonomers to produce gels that can undergo such volume transi- tions in response to other external stimuli such as pH, electric field and light. [5–7] Hydrogels based on these stimuli-sensitive materials have been investigated for con- trolled gene, [8] peptide [9] and drug deliv- ery, [10] protein purification, [11] sensors, [12] and chromatography. [13] We have been developing an auto- nomous, glucose-powered hydrogel-based device for rhythmic, pulsed release of gona- dotropin releasing hormone (GnRH) that utilizes pH-sensitive copolymers of N- isopropylacrylamide and carboxylic acids. [14–17] For example, copolymer hydrogels consisting of poly(N-isopropylacrylamide-co-methacrylic acid) [poly(NIPA-co-MAA)] with 10 mol.% MAA exhibit a volume transition (VT) at 37 8C around pH 5.0. [15] When these hydrogels are cast as membranes, they exhibit sharp changes in permeability to glucose near pH 5.0. [14–18] Placing such a membrane into a side-by-side diffusion cell (see Figure 1), with the donor side fed continuously with constant concentration glucose solution at pH 7.4, and with the receptor cell containing glucose oxidase and solid marble (CaCO 3 ), pH oscillations in the receptor cell are generated. [16,19] Further, when GnRH is incorporated into the receptor cell, the hormone is released in rhythmic pulses that are co- herent with the pH oscillations, indicating Macromol. Symp. 2007, 254, 338–344 DOI: 10.1002/masy.200750849 338 1 Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA E-mail: siege017@umn.edu 2 Department of Pharmaceutics, 308 Harvard St. SE, 9-127 WDH, University of Minnesota, Minneapolis, MN 55455, USA Copyright ß 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim