SMART Polymer Fibers For Tampon-Like Nonsteroidal Contraceptive Devices

用于卫生棉条类非甾体避孕器具的 SMART 聚合物纤维

• 批准号: 10018524
• 负责人: GIOVANNI M PAULETTI
• 金额: $ 34.09万
• 依托单位: ST. LOUIS COLLEGE OF PHARMACY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018524
• 关键词: Acids; Adhesives; Animal Model; Artificial Insemination; Biocompatible Materials; Biological Assay; Biological Markers; Biomedical Engineering; Buffers; Cells; Characteristics; Chemicals; Contraceptive Devices; Contraceptive Usage; Contraceptive methods; Data; Devices; Dose; Electrospinning; Embryo; Ensure; Environment; Evaluation; Exhibits; Exposure to; Feedback; Female; Fertility; Fertilization; Fiber; Future; Gel; Goals; Health; Human; In Vitro; Infertility; Inflammatory; Internet; Intravaginal Administration; Lead; Liquid substance; Measures; Methylcellulose; Morphology; Natural Fertility; Oryctolagus cuniculus; Perception; Performance; Pharmaceutical Chemistry; Phase; Physiological; Polymers; Process; Program Development; Property; Research; Risk; Safety; Self Administration; Seminal Plasma; Seminal fluid; Sensory; Site; Sperm Capacitation; Sperm Motility; Surveys; System; Tampons; Testing; Thick; Time; Tissue Model; Tissues; Vagina; Viscosity; Woman; acrylic acid; alkalinity; contraceptive efficacy; cost; crosslink; cytokine; cytotoxicity; high reward; high risk; implantation; in vivo; innovation; irritation; men; novel; prevent; prototype; reconstitution; reproductive; reproductive tract; safety assessment; sperm cell; unintended pregnancy; uptake; vaginal fluid; vaginal microbiome; viscoelasticity

PROJECT SUMMARY/ABSTRACT Natural fertility requires spermatozoa to migrate through viscoelastic secretions and to overcome the physiolog- ical acidic environment of the female reproductive tract. Our preliminary data show that novel mucoadhesive, bioresponsive polymer compositions maintain a physiologically acidic pH environment upon exposure to seminal fluid and, at the same time, dramatically increase viscoelastic properties, which negatively impacts sperm motil- ity. Therefore, it is hypothesized that - upon exposure to semen - the novel mucoadhesive, bioresponsive com- position rapidly transforms the vaginal cavity into an inhospitable environment for sperm. We propose to explore an innovative approach to on-demand non-steroidal contraception for women using SMART (= System Mute until Activation by a Remote Trigger) polymer fibers that maintain a physiological, protective vag- inal environment upon exposure to seminal fluid resulting in infertility. This high-risk/high-reward research strategy is fundamentally different from conventional nonsteroidal contraceptive methods as it represents an innovative bioengineering concept intended to reach the human testing phase (i.e., IND milestone) much faster and at a lower cost than conventional development programs focusing on medicinal chemistry approaches. In the R61 Phase, we will test whether non-woven fiber mats comprised of bioresponsive polymer mixtures establish an acidic mucoadhesive gel phase upon exposure to vaginal fluid that maintains a physiologically pro- tective highly viscous, acidic milieu in the presence of semen, thereby inhibiting sperm motility to a level con- sistent with infertility. The feasibility of this approach has been shown using polymeric fiber mats produced by electrospinning that demonstrated rapid conversion into a gel phase, which maintained acidic properties upon exposure to alkaline seminal fluid while, simultaneously, increasing 5-fold in viscosity. In Aim #1, we will delineate electrospinning fabrication parameters required to prepare dry, non-woven fiber mats that exhibit desired muco- adhesive and bioresponsive properties. We will test their ability to rapidly reconstitute into an acidic gel phase and maintain effective physical and chemical barriers properties for human sperm that are consistent with infer- tility. In Aim #2, we will define safety risks of non-woven polymeric fiber mats for nonsteroidal contraception. We will assess whether polymeric fiber mats are toxic to cells of the female reproductive tract. In addition, we will explore human factors that contribute to use-related safety and efficacy risks using internet surveys. The R33 Phase will be initiated only if quantitative milestones defined for the R61 Phase are met. In Aim #3, we will refine electrospinning fabrication process and perform a more rigorous in vitro safety assessment that includes inter- actions with the vaginal microbiome. In the final Aim #4, we will determine the safety, tolerability, and contracep- tive efficacy of the most promising polymer composition in vivo using the rabbit animal model.

项目摘要/摘要 自然生育需要精子通过粘弹性分泌物迁移，并克服生理障碍-- 雌性生殖道的酸性环境。我们的初步数据显示，新型粘附剂， 生物响应性聚合物组合物在暴露于精液时保持生理酸性pH环境 流体，同时，显著增加粘弹性，这对精子运动产生负面影响- 城市。因此，假设在接触精液后，这种新型的粘附性、生物响应性组件- 体位会迅速将阴道腔转变为不适合精子生长的环境。我们建议探索 使用SMART(=系统)为妇女提供按需非类固醇避孕的创新方法 静音直到被远程触发器激活)保持生理的、保护性的拱顶的聚合物纤维- 暴露在精液中会导致不育。这项高风险/高回报的研究 该策略与传统的非类固醇避孕方法有根本的不同，因为它代表了一种 创新的生物工程概念，旨在更快地达到人体测试阶段(即IND里程碑) 而且成本低于专注于药物化学方法的传统开发计划。 在R61阶段，我们将测试无纺布纤维垫是否由生物响应性聚合物混合物组成 在接触阴道液时建立酸性粘附性凝胶相，以保持生理上的亲和性。 在有精液的情况下具有保护性的高粘性、酸性环境，从而将精子的活力抑制到与精液不同的水平。 与不孕不育相一致。这种方法的可行性已经通过使用由 电纺，表现出快速转化为凝胶相，保持酸性的 暴露在碱性精液中，同时，粘度增加了5倍。在目标1中，我们将描述 制备具有所需粘性的干燥非织造纤维毡所需的静电纺丝工艺参数 粘附性和生物响应性。我们将测试它们快速重组为酸性凝胶相的能力 并保持人类精子的有效物理和化学屏障特性，这与推断- 实用程序。在目标2中，我们将定义用于非类固醇避孕的非织造聚合物纤维垫的安全风险。我们 将评估聚合物纤维垫是否对女性生殖道细胞有毒。此外，我们还将 通过互联网调查，探索导致与使用相关的安全性和有效性风险的人为因素。R33 只有在达到为R61阶段定义的量化里程碑时，才会启动阶段。在目标3中，我们将改进 电纺制造工艺，并进行更严格的体外安全评估，包括 与阴道微生物群的作用。在最终目标4中，我们将确定安全性、耐受性和避孕器- 最有希望的聚合物组合物在活体动物模型中的疗效。