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: 10474635
• 负责人: GIOVANNI M PAULETTI
• 金额: $ 80.41万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474635
• 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.

项目总结/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。 女性生殖道的酸性环境。我们的初步数据表明，新的粘膜粘附剂， 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 同时，也是一个很好的例子。 ity。因此，假设-在暴露于精液时-新的粘膜粘附性生物反应性化合物- 这种姿势会迅速将阴道腔变成一个不适合精子生存的环境。我们建议探索 一种创新的方法，为使用SMART（=系统）的女性提供按需非甾体避孕 静音，直到通过远程触发激活）聚合物纤维，保持生理，保护性vag- 在暴露于精液导致不育的最终环境中。这种高风险/高回报的研究 该策略与传统的非甾体避孕方法有根本的不同， 旨在达到人体测试阶段的创新生物工程概念（即，IND里程碑）快得多 并且成本低于专注于药物化学方法的常规开发计划。 在R61阶段，我们将测试由生物响应聚合物混合物组成的非织造纤维垫是否 在暴露于阴道液时建立酸性粘膜粘附凝胶相， 在精液存在的情况下，保护性的高粘性酸性环境，从而抑制精子活力到一定水平， 与不孕症相一致。这种方法的可行性已经通过使用聚合物纤维垫被证明， 电纺丝显示出快速转化成凝胶相，其在电纺丝后保持酸性。 暴露于碱性精液，同时粘度增加5倍。在目标#1中，我们将描述 制备表现出期望的粘膜粘附性的干燥非织造纤维垫所需的电纺丝制造参数。 粘合和生物响应性能。我们将测试它们快速重组成酸性凝胶相的能力 并为人类精子保持有效的物理和化学屏障特性， tility。在目标#2中，我们将定义用于非甾体避孕的非织造聚合物纤维垫的安全性风险。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，我们会 使用互联网调查探索导致使用相关安全性和有效性风险的人为因素。R33 仅当满足R61阶段定义的定量里程碑时，才启动阶段。在目标#3中，我们将改进 静电纺丝制造工艺，并进行更严格的体外安全性评估，包括内部 对阴道微生物组的作用。在最终的目标#4中，我们将确定安全性，耐受性和避孕药- 最有希望的聚合物组合物在体内使用兔动物模型的有效功效。