Manufacture and Assembly of Thermoplastic, Modular, Integrated Fluidic Systems

精准医学生物模块多尺度系统生物技术资源中心(CBM2) 研发3：热塑性、模块化、集成流体系统的制造和组装 摘要/摘要 液体活组织检查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，是他们对 联合分子检测。使用台式仪器时，质量限制尤其成问题 关联的样本处理。大多数基于液体活组织检查的分子分析需要多个步骤，每个步骤 复杂的工作流程，以及转移少量目标的额外问题，如DNA， RNA，或蛋白质，从一个仪器到另一个仪器。混合尺度的射流系统提供了压缩的潜力 将整套分析整合到单个集成平台中，减少了样品损失、操作员专业知识和 更简单的工作流程。CBM2的目标是开发技术，使模块化的集成系统可用 用于常规临床使用，即使是数量有限的样品。从该项目发展而来的技术将减少 构建和运营专门为以下目的而设计的集成和模块化射流系统的复杂性 分析液体活检标记物。 为了降低构建这类系统的复杂性，平台应该有利于规模化 生产，这表明使用注塑热塑性塑料。模块化的概念促进了这一点 通过将相同或相似的模块用于不同的检测，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主板。研发3的重点是 开发注塑主板和模块的制造和组装技术。 高热膨胀金属将实现坚固的混合比例模具插入，并降低脱模压力。一个 一种新型、可扩展、可重复、快速的盖板与聚合物基板热粘接方法 将使用包含流体网络(压力辅助、沸点热熔接(PABP TFB)) 这带来了高工艺成品率。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主板之间可靠地传递 无损耗，不需要O形圈或垫圈。为了消除对垫圈的需要， 模块化系统将使用无垫圈的超疏水流体互连，将精密 对齐部件以设置间隙&lt；10微米，在流体周围的表面上覆盖超疏水薄膜 通过。密封是毛细管力的函数，具有可预测的失效压力，并且可以传输 生物流体，如血浆和血液，以及从模块到主板的试剂。无垫圈互连 容忍在正常制造过程中发生的偏差；在续订申请中的努力 将确定范围是什么和最大失效压力。 为了展示模块化流体系统的威力，研发3将制造和组装一台 完整的模块化系统，将丰富循环中的肿瘤细胞(CTCs)并对其中的某些基因进行测序 基因组。该系统将有五个模块连接到一个通用主板上，并处理血液样本 电子读出选定的CTC基因，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.