? The long-term goal of the proposed research is to develop an implantable polymeric device, which delivers gonadotropin releasing hormone(GnRH, aka leuteinizing hormone release hormone, or LHRH) in periodic pulses, mimicking the normal, ultradian endogenous rhythm. Rhythmic pulsed administration of GnRH has been used successfully in the induction of ovulation in amenorrhic women, and in the induction of puberty and maintenance of sexual maturity in both males and females with hypogonadotropic hypogonadism (HH), while continuous administration of GnRH fails. Present pulsatile treatment is administered using wearable pumps, with cutaneous breach by a catheter. For patients who must receive pulsatile GnRH for many years, this mode of delivery leads to significant inconvenience and danger of infection. The proposed device could be implanted subcutaneously or intraperitoneally, and may function for months or years. It is hoped that implantation will ameliorate the disadvantages of pump/catheter systems. The device concept features a hydrogel membrane, which undergoes periodic swelling-deswelling cycles, due to a feedback interaction between the membrane with the enzyme glucose oxidase. Release occurs during the swollen phase of the cycle. Oscillations are """"""""fueled"""""""" by endogenous glucose at the site of implantation, whose level fluctuates only moderately in nondiabetics. (Rhythmic behavior of this device is distinguished from the glucose-responsive behavior of closed-loop insulin delivery devices.) While the feasibility of this concept has been confirmed in a model system, considerable work remains in converting the concept to a workable device that can be tested in patients. The specific goal of this proposal is to produce a prototype system whose properties can be tested in an in vitro environment that emulates in vivo conditions. In pursuing this goal, effects of the hydrogel membrane composition and thickness, the enzyme reaction, the device geometry, and the molecular properties of GnRH on the pulsatile release pattern will be studied. We will investigate device behavior in buffers and simulated plasma, when challenged with constant levels of glucose and programs of glucose fluctuations that are observed in nondiabetic individuals. ? ?
