Manufacture and Assembly of Thermoplastic, Modular, Integrated Fluidic Systems

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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.