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Quantitative detection of various molecules at very low concentrations in complex mixtures has been the main objective in many fields of science and engineering, from the detection of cancer-causing mutagens and early disease markers to environmental pollutants and bioterror agents 1 – 5 . Moreover, technologies that can detect these analytes without external labels or modifications are extremely valuable and often preferred 6 . In this regard, surface-enhanced Raman spectroscopy can detect molecular species in complex mixtures on the basis only of their intrinsic and unique vibrational signatures 7 . However, the development of surface-enhanced Raman spectroscopy for this purpose has been challenging so far because of uncontrollable signal heterogeneity and poor reproducibility at low analyte concentrations 8 . Here, as a proof of concept, we show that, using digital (nano)colloid-enhanced Raman spectroscopy, reproducible quantification of a broad range of target molecules at very low concentrations can be routinely achieved with single-molecule counting, limited only by the Poisson noise of the measurement process. As metallic colloidal nanoparticles that enhance these vibrational signatures, including hydroxylamine–reduced-silver colloids, can be fabricated at large scale under routine conditions, we anticipate that digital (nano)colloid-enhanced Raman spectroscopy will become the technology of choice for the reliable and ultrasensitive detection of various analytes, including those of great importance for human health. Research published in Nature shows that surface-enhanced Raman spectroscopy carried out with colloids can quantify a range of molecules down to concentrations at the femtomolar level.

Chain reactions, characterized by initiation, propagation and termination, are stochastic at microscopic scales and underlie vital chemical (for example, combustion engines), nuclear and biotechnological (for example, polymerase chain reaction) applications 1 , 2 , 3 , 4 – 5 . At macroscopic scales, chain reactions are deterministic and limited to applications for entertainment and art such as falling dominoes and Rube Goldberg machines. On the other hand, the microfluidic lab-on-a-chip (also called a micro-total analysis system) 6 , 7 was visualized as an integrated chip, akin to microelectronic integrated circuits, yet in practice remains dependent on cumbersome peripherals, connections and a computer for automation 8 , 9 , 10 – 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 , 13 , 14 , 15 , 16 , 17 , 18 – 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 three-dimensionally printed, and powered by the free energy of a paper pump, autonomously execute liquid handling algorithms step-by-step. With MCR, we automated (1) the sequential release of 300 aliquots across chained, interconnected chips, (2) a protocol for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) antibodies detection in saliva and (3) 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 a frugal, versatile, bona fide lab-on-a-chip with wide-ranging applications in liquid handling and point-of-care diagnostics. Microfluidic chain reactions encode programs structurally in situ, and can form a frugal, versatile, bona fide lab-on-a-chip with wide-ranging applications in liquid handling and point-of-care diagnostics

Collective guidance of out-of-equilibrium systems without using external fields is a challenge of paramount importance in active matter, ranging from bacterial colonies to swarms of self-propelled particles. Designing strategies to guide active matter and exploiting enhanced diffusion associated to its motion will provide insights for application from sensing, drug delivery to water remediation. However, achieving directed motion without breaking detailed balance, for example by asymmetric topographical patterning, is challenging. Here we engineer a two-dimensional periodic topographical design with detailed balance in its unit cell where we observe spontaneous particle edge guidance and corner accumulation of self-propelled particles. This emergent behaviour is guaranteed by a second-order non-Hermitian skin effect, a topologically robust non-equilibrium phenomenon, that we use to dynamically break detailed balance. Our stochastic circuit model predicts, without fitting parameters, how guidance and accumulation can be controlled and enhanced by design: a device guides particles more efficiently if the topological invariant characterizing it is non-zero. Our work establishes a fruitful bridge between active and topological matter, and our design principles offer a blueprint to design devices that display spontaneous, robust and predictable guided motion and accumulation, guaranteed by out-of-equilibrium topology. Sustainable strategies for shepherding active particles are at the heart of many prospective applications. Here, Palacios et al. use the emerging topological properties of a microfluidic maze array to passively guide self-propelled colloids from the interior to the edges of the device.

Fluorescence analysis is a fast and sensitive method, and has great potential application in trace detection of environmental toxins. However, many important environmental toxins are non-fluorescent substances, and it is still a challenge to construct a fluorescence detection method for non-fluorescent substances. Here, by means of charge transfer effect and smart molecular imprinting technology, we report a sensitive indirect fluorescent sensing mechanism (IFSM) and microcystin (MC-RR) is selected as a model target. A molecular imprinted thin film is immobilized on the surface of zinc ferrite nanoparticles (ZnFe 2 O 4 NPs) by using arginine, a dummy fragment of MC-RR. By implementation of IFSM on the paper-based microfluidic chip, a versatile platform for the quantitative assay of MC-RR is developed at trace level (the limit of detection of 0.43 μg/L and time of 20 min) in real water samples without any pretreatment. Importantly, the proposed IFSM can be easily modified and extended for the wide variety of species which lack direct interaction with the fluorescent substrate. This work offers the potential possibility to meet the requirements for the on-site analysis and may explore potential applications of molecularly imprinted fluorescent sensors. Fluorescence analysis is a fast and sensitive method for the trace detection of environmental toxins, but it remains challenging to develop a fluorescence method for detecting nonfluorescent toxins. Here, the authors report an indirect fluorescent sensing strategy for the rapid, selective and sensitive detection of the non-fluorescent microcystin as a model target.

The detection and identification of bacteria currently rely on enrichment steps such as bacterial culture and nucleic acid amplification to increase the concentration of target analytes. These steps increase assay time, cost and complexity, making it difficult to realize a truly rapid point-of-care test. Here we report the development of an electrical assay that uses electroactive RNA-cleaving DNAzymes (e-RCDs) to identify specific bacterial targets and subsequently release a DNA barcode for transducing a signal onto an electrical chip. Integrating e-RCDs into a two-channel electrical chip with nanostructured electrodes provides the analytical sensitivity and specificity needed for clinical analysis. The e-RCD assay is capable of detecting 10 CFU (equivalent to 1,000 CFU ml–1) of Escherichia coli selectively from a panel containing multiple non-specific bacterial species. Clinical evaluation of this assay using 41 patient urine samples demonstrated a diagnostic sensitivity of 100% and specificity of 78% at an analysis time of less than one hour compared with the several hours needed for currently used culture-based methods.Methods to detect and identify bacteria typically rely on enrichment steps such as bacterial culture and nucleic acid amplification. Now, an assay for detecting bacteria based on a two-channel electrical chip that combines electroactive DNAzymes with an electrochemical readout, has been developed. This assay enables reagentless and culture-free detection of bacteria in clinical samples.

Mid-infrared spectroscopy is a sensitive and selective technique for probing molecules in the gas or liquid phase. Investigating chemical reactions in bio-medical applications such as drug production is recently gaining particular interest. However, monitoring dynamic processes in liquids is commonly limited to bulky systems and thus requires time-consuming offline analytics. In this work, we show a next-generation, fully-integrated and robust chip-scale sensor for online measurements of molecule dynamics in a liquid solution. Our fingertip-sized device utilizes quantum cascade technology, combining the emitter, sensing section and detector on a single chip. This enables real-time measurements probing only microliter amounts of analyte in an in situ configuration. We demonstrate time-resolved device operation by analyzing temperature-induced conformational changes of the model protein bovine serum albumin in heavy water. Quantitative measurements reveal excellent performance characteristics in terms of sensor linearity, wide coverage of concentrations, extending from 0.075 mg ml −1 to 92 mg ml −1 and a 55-times higher absorbance than state-of-the-art bulky and offline reference systems. Rapid investigation of chemical reactions is a challenge in bio-medical analysis. Here, the authors demonstrate sensitive in-situ real-time reaction-monitoring of conformational changes in protein solution, based on a fingertip-sized mid-IR lab-on-a-chip.

Microfluidic paper-based analytical devices (µPADs) have provided a breakthrough in portable and low-cost point-of-care diagnostics. Despite their significant scope, the complexity of fabrication and reliance on expensive and sophisticated tools, have limited their outreach and possibility of commercialization. Herein, we report for the first time, a facile method to fabricate µPADs using a commonly available laser printer which drastically reduces the cost and complexity of fabrication. Toner ink is used to pattern the µPADs by printing, without modifying any factory configuration of the laser printer. Hydrophobic barriers are created by heating the patterned paper which melts the toner ink, facilitating its wicking into the cross-section of the substrate. Further, we demonstrate the utilization of the fabricated device by performing two assays. The proposed technique provides a versatile platform for rapid prototyping of µPADs with significant prospect in both developed and resource constrained region.

DNA hydrogels have received considerable attention in analytical science, however, some limitations still exist in the applications of intelligent hydrogels. In this paper, we describe a way to prepare gel film in a capillary tube based on the thermal reversible principle of DNA hydrogel and the principle of capillary action. Because of the slight change in the internal structure of gel, its permeability can be increased by the addition of some specific targets. The capillary behavior is thus changed due to the different permeability of the hydrogel film. The duration time of the target solution flowing through the capillary tube with a specified length is used to quantify this change. With this proposed method, ultra-trace DNA hydrogel (0.01 μL) is sufficient to realize the sensitive detection of cocaine without the aid of other instruments, which has a low detection limit (1.17 nM) and good selectivity. DNA hydrogels have received considerable attention in analytical science but limitations still exist in the applications of intelligent hydrogels. Here, the authors describe a DNA hydrogel sensor for quantitative detection of cocaine based on the permeability change in a DNA hydrogel film.

The recent Zika virus (ZIKV) outbreak has prompted the need for field-ready diagnostics that are rapid, easy-to-use, handheld, and disposable while providing extreme sensitivity and specificity. To meet this demand, we developed a wax-printed paper microfluidic chip utilizing reverse transcription loop-mediated isothermal amplification (RT-LAMP). The developed simple and sensitive ZIKV assay was demonstrated using undiluted tap water, human urine, and diluted (10%) human blood plasma. Paper type, pore size, and channel dimension of various paper microfluidic chips were investigated and optimized to ensure proper filtration of direct-use biological samples (tap water, urine, and plasma) during capillary action-driven flow. Once ZIKV RNA has flowed and reached to a detection area of the paper microfluidic chip, it was excised for the addition of an RT-LAMP mixture with a pH indicator, then placed on a hot plate at 68 °C. Visible color changes from successful amplification were observed in 15 minutes and quantified by smartphone imaging. The limit of detection was as low as 1 copy/μL. The developed platform can also be used for identifying other flaviviruses, such as Chikungunya virus (CHIKV) and Dengue virus (DENV), and potentially other quickly transmitted virus pathogens, towards field-based diagnostics.

Despite substantial advances in sensing technologies, the development, preparation, and use of self-testing devices is still confined to specialist laboratories and users. Decentralized analytical devices will enormously impact daily lives, enabling people to analyze diverse clinical, environmental, and food samples, evaluate them and make predictions to improve quality of life, particularly in remote, resource-scarce areas. In recent years, paper-based analytical tools have attracted a great deal of attention; the well-known properties of paper, such as abundance, affordability, lightness, and biodegradability, combined with features of printed electrochemical sensors, have enabled the development of sustainable devices that drive (bio)sensors beyond the state of the art. Their blindness toward colored/turbid matrices (i.e., blood, soil), their portability, and the capacity of paper to autonomously filter/purge/react with target species make such devices powerful in establishing point-of-need tools for use by non-specialists. This protocol describes the preparation of a voltammetric phosphate sensor and an amperometric nerve agent biosensor; both platforms produce quantitative measurements with currents in the range of microamperes. These printed strips comprise three electrodes (graphite for working and counter electrodes and silver/silver chloride (Ag/AgCl) for the reference electrode) and nanomodifiers (carbon black and Prussian blue) to improve their performance and specificity. Depending on analytical need, different types of paper (filter, office) and configurations (1D, 2D, 3D) can be adopted. The protocol, based on the use of cost-effective manufacturing techniques such as drop casting (to chemically modify the substrate surface) and wax/screen printing (for creating the channels and electrodes), can be completed in <1 h.