Manufacture and Assembly of Thermoplastic, Modular, Integrated Fluidic Systems

标题：精准医学生物模块化多尺度系统（CBM 2）生物技术资源中心 TR&D 3：热塑性塑料、模块化、集成流体系统的制造和组装 摘要/概要 液体活检标记物应用于各种临床问题的主要限制之一， 如癌症、中风和耐药细菌感染，是它们对人类造成的质量限制。 相关分子测定。当使用台式仪器时，质量限制特别成问题， 相关的样品处理。大多数基于液体活检的分子测定需要多个步骤，每个步骤 由于复杂的工作流程，以及转移少量目标，如DNA， RNA或蛋白质，从一台仪器到另一台仪器。混合规模的流体系统提供了压缩 将整套检测系统整合到一个集成平台中，减少样本丢失、操作员专业知识， 更简单的工作流程。CBM 2的目标是开发技术以提供模块化、集成的系统 用于常规临床使用，甚至用于质量有限的样品。从该项目发展而来的技术将减少 构建和操作集成和模块化流体系统的复杂性， 分析液体活检标记物。 为了降低构建此类系统的复杂性，平台应有利于大规模 生产，这表明使用注塑成型的热塑性塑料。模块化概念有助于实现这一点 通过将相同或相似的模块用于不同的测定，能够将模块用作独立单元， 以及包含标准化互连以容纳模块的母板。TR&D 3的重点是 开发注塑成型主板和模块的制造和组装技术。 高热膨胀金属将使强大的混合规模模具插入和减少脱模应力。一 将盖板热粘合到聚合物基底上的新颖、可扩展、可重复和快速的方法 将使用含流体网络（压力辅助，沸点热熔粘合（PABP TFB）） 提供高的工艺产率。构建模块化系统的另一个挑战是确保 少量的目标DNA、RNA或蛋白质可以在模块和母板之间可靠地通过 没有损失并且消除了对O形环或垫圈的需要。为了消除对垫圈的需要， 模块化系统将使用无衬垫的超疏水流体互连，这种互连将联合收割机的精确性 对齐组件以设置<10 µm的间隙，在流体周围的表面上具有超疏水膜 个通道好吗密封是毛细管力的函数，具有可预测的失效压力，并且可以输送 生物流体，例如血浆和血液，以及从模块到母板的试剂。该无垫片互连件 能够容忍正常制造过程中出现的错位;在更新申请中所做的努力 将确定范围和最大失效压力。 为了展示模块化流体系统的力量，TR&D 3将制造和组装一个 一个完整的模块化系统，将丰富循环肿瘤细胞（CTC）和测序某些基因在其 基因组该系统将有五个模块连接到一个通用主板和处理血液样本 到CTC的选定基因的电子读数，为临床医生提供可操作的信息。

TITLE: Biotechnology Resource Center of BioModular Multi-scale Systems (CBM2) for Precision Medicine TR&D 3: Manufacture and Assembly of Thermoplastic, Modular, Integrated Fluidic Systems Abstract/Summary One of the primary limitations in the application of liquid biopsy markers to a diverse set of clinical problems, such as cancer, stroke, and drug-resistant bacterial infections, is the mass-limits they impose on the associated molecular assays. Mass limits are particularly problematic when using benchtop instruments and the associated sample handling. Most liquid biopsy-based molecular assays require multiple steps, each with a complex workflow, and the added problem of transferring small quantities of targets, such as DNA, RNA, or proteins, from one instrument to the next. Mixed-scale fluidic systems offer the potential to compress the entire set of assays into a single, integrated platform reducing sample loss, operator expertise, and simpler workflows. The goal of CBM2 is to develop technologies to make modular, integrated systems available for routine clinical use, even for mass-limited samples. Technologies evolving from this project will reduce the complexity of building and operating integrated and modular fluidic systems specifically designed to analyze liquid biopsy markers. In order to reduce the complexity of building such systems, the platforms should be conducive to high-scale production, which points to the use of injection molded thermoplastics. The modular concept facilitates this by using the same or similar modules for different assays, ability to use the modules as standalone units, and a motherboard containing standardized interconnects to host the modules. The focus of TR&D 3 is to develop technologies for manufacturing and assembly of injection molded motherboards and modules. High thermal expansion metals will enable robust mixed-scale mold inserts and reduce demolding stresses. A novel, scalable, repeatable and rapid method of thermally bonding cover plates to polymer substrates containing fluid networks (pressure assisted, boiling point thermal fusion bonding (PABP TFB)) will be used that delivers high process yield rates. Another challenge for building modular systems is to ensure that the small quantities of target DNA, RNA, or proteins can pass reliably between modules and the motherboard without loss and eliminating the need for O-rings or gaskets. To eliminate the need for gaskets, the modular systems will use gasketless superhydrophobic fluid interconnects that combine precision alignment of components to set gaps <10 µm, with superhydrophobic films on the surfaces around a fluid passage. The seal is a function of capillary forces, has a predictable failure pressure, and can transport biofluids, such as plasma and blood, and reagents from module to motherboard. The gasketless interconnect is tolerant of misalignment, which occurs in normal manufacturing processes; efforts in the renewal application will establish what the range is and the maximum failure pressure. To demonstrate the power of the modular fluidic systems, TR&D 3 will manufacture and assemble a complete modular system that will enrich circulating tumor cells (CTCs) and sequence certain genes in their genome. The system will have five modules connected to a universal motherboard and process a blood sample to an electronic readout of selected genes of the CTCs, providing actionable information for clinicians.