Microfluidic Chain Reaction: Conditional, Structurally Programmed Propagation of Capillary Flow Events

Chain reactions are characterized by initiation, propagation and termination, are stochastic at microscopic scales and underlie vital chemical (e.g. combustion engines), nuclear and biotechnological (e.g. polymerase chain reaction) applications.1-5 At macroscopic scales, chain reactions are deterministic and limited to applications for entertainment and art such as falling domino and Rube Goldberg machines. Appositely, the microfluidic lab-on-a-chips (also called a micro total analysis system),6,7 was envisioned as an integrated chip, akin to microelectronic integrated circuits, yet in practice remain dependent on cumbersome peripherals, connections, and a computer for automation.8-11 Capillary microfluidics integrate energy supply and flow control onto a single chip by using capillary phenomena, but programmability remains rudimentary with at most a handful (eight) operations possible.12-19 Here we introduce the microfluidic chain reaction (MCR) as the conditional, structurally programmed propagation of capillary flow events. Monolithic chips integrating a MCR are 3D printed, and powered by the free-energy of a paper pump, autonomously execute liquid handling algorithms step-by-step. With MCR, we automated (i) the sequential release of 300 aliquots across chained, interconnected chips, (ii) a protocol for SARS-CoV-2 antibodies detection in saliva, and (iii) a thrombin generation assay by continuous subsampling and analysis of coagulation-activated plasma with parallel operations including timers, iterative cycles of synchronous flow and stop-flow operations. MCRs are untethered from and unencumbered by peripherals, encode programs structurally in situ, and can form frugal, versatile, bona fide lab-on-a-chip with wide-ranging applications in liquid handling and point-of-care diagnostics.