title: Mechanistic studies of an autonomously pulsing hydrogel/enzyme system for rhythmic hormone delivery.
abstract: Numerous hormones are known to be endogenously secreted in a pulsatile manner. In particular, gonadotropin replacing hormone (GnRH) is released in rhythmic pulses, and disruption of this rhythm is associated with pathologies of reproduction and sexual development. In an effort to develop an implantable, rhythmic delivery system, a scheme has been demonstrated involving a negative feedback instability between a pH-sensitive membrane and enzymes that convert endogenous glucose to hydrogen ion. A bench prototype system based on this scheme was previously shown to produce near rhythmic oscillations in internal pH and in GnRH delivery over a period of one week. In the present work, a systematic study of conditions permitting such oscillations is presented, along with a study of factors causing period of oscillations to increase with time and ultimately cease. Membrane composition, glucose concentration, and surface area of marble (CaCO3), which is incorporated as a reactant, were found to affect the capacity of the system to oscillate, and the pH range over which oscillations occur. Accumulation of gluconate- and Ca2+ in the system over time correlated with lengthening of oscillation period, and possibly with cessation of oscillations. Enzyme degradation may also be a factor. These studies provide the groundwork for future improvements in device design.
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Amardeep S
authors.initials: AS
authors.lastname: Bhalla
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA; Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: siege017@umn.edu.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Siegel
mesh_terms: D002021:Buffers; D002118:Calcium / Q000737:chemistry; D002119:Calcium Carbonate / Q000737:chemistry; D016503:Drug Delivery Systems; D004798:Enzymes / Q000737:chemistry*; D005947:Glucose / Q000032:analysis / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000493:pharmacokinetics; D006728:Hormones / Q000008:administration & dosage*; D020100:Hydrogels / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D008567:Membranes, Artificial
chemical_list: D002021:Buffers; D004798:Enzymes; D006728:Hormones; D020100:Hydrogels; D008567:Membranes, Artificial; D007987:Gonadotropin-Releasing Hormone; D002119:Calcium Carbonate; D005947:Glucose; D002118:Calcium
keywords: Enzyme mediated drug delivery; GnRH; Membrane; Membrane permeability; Rhythmic hormone delivery; pH-oscillator; pH-sensitive hydrogels