Episodic Release of GnRH from Pulsating Hydrogels

描述(由申请人提供)： 这项拟议研究的长期目标是开发一种植入型聚合物设备，它在周期性脉冲中传递促性腺激素释放激素(GnRH，又名亮氨酸激素释放激素，或LHRH)，模拟正常的、超传统的内源性节律。GnRH节律性脉冲给药已成功地用于闭经妇女的排卵诱导，以及性腺激素低减(HH)的男性和女性的青春期诱导和性成熟的维持，而持续GnRH给药失败。目前的脉动治疗是使用可穿戴式泵进行的，皮肤破裂通过导管进行。对于必须接受多年搏动性促性腺激素释放激素的患者，这种分娩方式会带来极大的不便和感染的危险。建议的装置可以植入皮下或腹膜内，可能会工作几个月或几年。植入物有望改善泵/导管系统的缺点。该装置的概念是水凝胶膜，由于膜与葡萄糖氧化酶之间的反馈作用，水凝胶膜经历周期性的溶胀-脱水循环。释放发生在周期的膨胀阶段。振荡是由植入部位的内源性葡萄糖“推动”的，在非糖尿病患者中，内源性葡萄糖的水平只有适度的波动。(这种装置的节律性行为有别于闭环式胰岛素输送装置的葡萄糖反应行为。)虽然这一概念的可行性已经在模型系统中得到证实，但在将这一概念转化为可在患者身上测试的可行装置方面仍有大量工作要做。这项提议的具体目标是生产一种原型系统，其特性可以在模拟体内条件的体外环境中进行测试。在追求这一目标的过程中，将研究水凝胶膜的组成和厚度、酶的反应、装置的几何形状和GnRH的分子性质对脉动释放模式的影响。我们将研究设备在缓冲液和模拟血浆中的行为，当受到恒定的血糖水平和非糖尿病患者观察到的血糖波动程序的挑战时。

DESCRIPTION (provided by applicant): 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.