ADDITIVE MANUFACTURING OF PDMS MICROFLUIDICS

由于人与人之间的生物差异，新疗法的开发在人体临床试验中经常失败 动物模型和目前的体外模型不能准确地概括体内状态。因此，体外微流控(MF) 模型有了显著的增长，并成为了解生物系统以及测试和开发 新疗法。然而，微流控技术的创新受到材料和制造挑战的限制 传统工艺，如软性光刻、注塑成型和机械球磨。加法制造(AM)，也称加法制造 作为3D打印，已被誉为这些制造挑战的解决方案，AM还提供广泛的设计 通过传统制造无法获得的自由。然而，AM面临着一个关键障碍：传统3D打印能力有限 (热固化)聚二甲基硅氧烷(PDMS)，最广泛的研发微流控材料。尽管有潜在的 尽管AM具有制造和设计方面的优势，但由于潜在的材料风险，AM尚未被广泛应用于MF生产。 在商业上可用的AM工艺和正在研究的工艺中，没有一种能为商业3D打印提供明确的途径 传统的PDMS中频设备。我们的假设是：将传统PDMS的知识库和熟悉度与我们的3D PDMS工艺将从根本上改变微流体的制造方式，并释放添加剂制造的设计自由度 对于MF社区，这将导致体外MF模型的重大进步。 在我们成功的第一阶段工作的基础上-在此期间我们展示了我们正在申请专利的3D PDMS工艺的能力 从传统的PDMS到3D打印MF设备-这个第二阶段的工作重点是开发一个中试规模的商业3D PDMS系统 并使用3D PDMS工艺制造尖端的体外血脑屏障模型，供我们在弗吉尼亚州的合作者测试 技术部。他们最近开发了一种包含纳米纤维基底膜模拟物的MF BBB模型，它展示了一种优越的 能够概括体内的血脑屏障结构。在第二阶段，该团队将优化纳米膜的架构，然后 设计并演示了一种可商业化生产的3D PDMS MF纳米膜BBB模型，该模型具有集成电极。我们还将 与哈佛大学麻省理工学院的Nadkarni小组合作，使用激光散斑表征3D PDMS打印中的PDMS固化动力学 流变学。 目标1：可运行的中试规模的三维PDMS系统。这个目标是设计和建立一个中试规模的3DPDMS 系统。里程碑1A：3D PDMS模拟和模型准确预测+/-10%内的固化；里程碑1A：3D PDMS模拟 模型准确地预测了+/-10%范围内的固化；里程碑1B：3DPDMS单元为MF设备实现了200 mm3/小时的构建速度。 目的2：3D打印纳米纤维血脑屏障模型。本发明目的是3D打印高度可重复性的血脑屏障 该模型结合了纳米纤维膜和集成的TEER电极。里程碑2A：纳米纤维的传输主曲线 膜的开发；里程碑2B：优化的纳米纤维BBB模型，通过联合 培养样本与单一培养样本的比较。 项目摘要/摘要

Development of new therapeutics often fails in human clinical trials due to the biological differences between humans and animal models and the inability of current in vitro models to accurately recapitulate the in vivo state. As such, in vitro microfluidic (MF) models have seen significant growth and become a key tool for understanding biological systems, and for testing and development of new therapeutics. Innovation in microfluidics, however, is limited by materials and manufacturing challenges associated with conventional processes such as soft lithography, injection molding, and mechanical milling. Additive manufacturing (AM), also referred to as 3D printing, has been heralded as the solution to these manufacturing challenges and AM additionally offers broad design freedom not accessible via conventional manufacturing. However, AM faces a critical hurdle: the limited ability to 3D print conventional (thermally-curable) polydimethylsiloxane (PDMS), the most widely established R&D microfluidic material. Despite the potential manufacturing and design benefits, AM has not been broadly adopted for MF production due in large part to the potential material risks. Of the commercially available AM processes and those being researched, none offer a clear path to commercial 3D printing of conventional PDMS MF devices. Our hypothesis is: combining the knowledge-base and familiarity of conventional PDMS with our 3D PDMS process will fundamentally change the way microfluidics are fabricated and unlock the design freedom of additive manufacturing for the MF community, which will lead to significant advancements of in vitro MF models. Building upon our successful Phase I effort — during which we demonstrated the ability of our patent-pending 3D PDMS process to 3D print MF devices from conventional PDMS — this Phase II effort focuses on developing a pilot-scale commercial 3D PDMS system and using the 3D PDMS process to fabricate cutting edge in vitro blood-brain-barrier models for testing by our collaborators at Virginia Tech. They recently developed a MF BBB model containing a nanofiber basement membrane mimic which demonstrates a superior ability to recapitulate the in vivo BBB architecture. In Phase II, the team will optimize the architecture of the nanomembranes and then design and demonstrate a commercially producible 3D PDMS MF nanomembrane BBB model with integrated electrodes. We will also collaborate with the Nadkarni group at Harvard MGH to characterize the PDMS curing kinetics in 3D PDMS printing using laser speckle rheology. Aim 1: Operational Pilot-Scale 3D PDMS System. The objective of this aim is to design and a build pilot-scale 3D PDMS system. Milestone 1A: 3D PDMS Simulation & Model Accurately Predict Curing within +/-10%; Milestone 1A: 3D PDMS Simulation Model Accurately Predicts Curing within +/-10%; Milestone 1B: 3D PDMS unit achieves 200 mm3/hr build rate for MF device. Aim 2: 3D Printed Nanofiber Blood-Brain-Barrier Model. The objective of this aim is to 3D print a highly reproducible BBB model which incorporates a nanofiber membrane and integrated TEER electrodes. Milestone 2A: Transport master curves for nanofiber membranes developed; Milestone 2B: Optimized nanofiber BBB model demonstrated by a 20% increase in TEER values for a co- culture sample as compared to a monoculture sample. Project Summary/Abstract