Innovative 3D Printed Intravaginal Rings: Reengineering Multipurpose Intravaginal Rings for Prevention of HIV, STIs and Unintended Pregnancy

摘要： 在全球范围内，50%以上的艾滋病毒感染者是妇女，每年约有50%的孕妇是 无意的。因此，迫切需要促进由女性控制的多用途避孕方法。 可以与性行为无关的预防和提供战略。阴道环 女性耐受，可有效用于避孕和激素替代疗法， 患者依从性[1-4]。然而，由于复杂性，开发有效的多用途IVR具有挑战性 当前工程工艺的差异[5，6]，以及药物性质和释放速率的差异，因此强制要求 药物特定的定制IVR设计。本提案的最终目标是通过以下方式解决这些限制： 使用已知的最先进的3D打印过程来革命性地改变阴道内环的工程过程， 作为连续液体界面生产（CLIP™）[7]。使用CLIP，我们可以设计具有复杂 这是传统注塑或挤出无法实现的几何形状。几何结构比较复杂 环内将使我们能够精确地微调药物从IVR的扩散和释放， 药物从IVR中完全释放。更重要的是，有了CLIP，我们可以制造多用途的IVRs， 可以整合2种或多种药物来预防意外怀孕和性传播感染（HIV、HSV-2、HPV） 一种快速且成本有效的单步方法。我们建议全面评估这一创新 使用粘膜猿猴/人类免疫缺陷病毒的高度相关猕猴模型的方法 （SHIV 162 p3）作为一种宝贵的临床前工具，用于评估IVR对SHIV感染的有效性[8- 10]。这种尖端的综合方法将被用来评估我们的建议的科学前提， 调查在持续提供服务的同时，是否可以沿着持续预防艾滋病毒感染 使用独特且高度创新的3D打印多用途IVR的避孕药。

Abstract: Globally, over 50% of those infected with HIV are women, and annually, ~50% of all pregnancies are unintended. Therefore, there is a critical need to promote female-controlled methods of multipurpose prevention and delivery strategies that can be disassociated from the sex act. Intravaginal rings are well tolerated by women, are efficacious for contraception and hormone replacement therapy, and have high patient compliance [1-4]. However, developing effective multipurpose IVRs is challenging due to the complexity of current engineering processes [5, 6], and differences in drug properties and release rates, thus mandating drug-specific customized IVR designs. The ultimate goal of this proposal is to address these limitations by revolutionizing the engineering process of intravaginal rings using a state-of-the-art 3D printing process known as the continuous liquid interface production (CLIP™) [7]. Using CLIP, we can engineer IVRs with complex geometries that cannot be achieved with traditional injection molding or extrusion. The complex geometries within the ring will allow us to precisely fine-tune diffusion and release of drugs from the IVR, and achieve near complete release of drugs from the IVR. More importantly, with CLIP, we can manufacture multipurpose IVRs that can integrate 2 or more drugs to prevent against unintended pregnancies and STIs (HIV, HSV-2, HPV) in a rapid and cost effective single-step process. We propose a comprehensive evaluation of this innovative approach using a highly relevant macaque model of mucosal simian/human immunodeficiency virus (SHIV162p3) as an invaluable preclinical tool to assess the efficacy of the IVRs against SHIV acquisition [8- 10]. This cutting edge combined approach will be utilized to evaluate the scientific premise of our proposal to investigate whether sustained protection against HIV acquisition can be achieved along with sustained delivery of a contraceptive drug using a unique and highly innovative 3D printed multipurpose IVR.