Episodic Release of GnRH from Pulsating Hydrogels

脉动水凝胶中 GnRH 的间歇性释放

• 批准号: 7026544
• 负责人: Ronald A Siegel
• 金额: $ 25.06万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7026544
• 关键词: artificial membranes; biomaterial compatibility; biomaterial development /preparation; biomaterials; biomedical equipment development; drug delivery systems; enzyme mechanism; gel; glucose oxidase; gonadotropin releasing factor; implant; medical implant science; miniature biomedical equipment; polymers; slow release drug

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.

描述（由申请人提供）： 拟议研究的长期目标是开发一种可植入的聚合物装置，其以周期性脉冲的方式递送促性腺激素释放激素（GnRH，又名促黄体激素释放激素或LHRH），模仿正常的超日内源性节律。GnRH的节律性脉冲给药已成功地用于无排卵妇女的排卵诱导，以及低促性腺激素性性腺功能减退症（HH）男性和女性的青春期诱导和性成熟的维持，而GnRH的连续给药失败。目前的脉动治疗是使用可穿戴的泵来管理的，其中通过导管进行皮肤突破。对于必须接受脉冲式GnRH多年的患者，这种输送方式会导致严重的不便和感染的危险。所提出的装置可以皮下或腹膜内植入，并且可以运行数月或数年。希望植入将改善泵/导管系统的缺点。该器械概念的特点是水凝胶膜，由于膜与葡萄糖氧化酶之间的反馈相互作用，水凝胶膜经历周期性溶胀-去溶胀循环。释放发生在循环的溶胀阶段。振荡是由植入部位的内源性葡萄糖“推动”的，其水平在非糖尿病患者中仅适度波动。（该装置的节律行为与闭环胰岛素输送装置的葡萄糖响应行为不同。）虽然这一概念的可行性已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进行测试的可行装置方面仍有大量工作要做。该提案的具体目标是产生一个原型系统，其特性可以在模拟体内条件的体外环境中进行测试。在追求这一目标时，将研究水凝胶膜组成和厚度、酶反应、装置几何形状和GnRH的分子性质对脉冲释放模式的影响。我们将研究在缓冲液和模拟血浆中，当在非糖尿病个体中观察到恒定水平的葡萄糖和葡萄糖波动程序时的器械行为。

项目成果

Macromolecular Diffusion in Self-Assembling Biodegradable Thermosensitive Hydrogels.

自组装可生物降解热敏水凝胶中的大分子扩散。

• DOI: 10.1021/ma902186e
• 发表时间: 2010
• 期刊: Macromolecules
• 影响因子: 5.5
• 作者: Vermonden,Tina;Jena,SidharthaS;Barriet,David;Censi,Roberta;vanderGucht,Jasper;Hennink,WimE;Siegel,RonaldA
• 通讯作者: Siegel,RonaldA

Introduction of pH-Sensitivity into Mechanically Strong Nanoclay Composite Hydrogels Based on N-Isopropylacrylamide.

• DOI: 10.1002/pola.22973
• 发表时间: 2008-10-01
• 期刊: JOURNAL OF POLYMER SCIENCE PART A-POLYMER CHEMISTRY
• 作者: Mujumdar, Siddharthya K.;Siegel, Ronald A.
• 通讯作者: Siegel, Ronald A.