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Recent progress in the various lab-on-a-chip microtechnologies is reviewed and the clinical and research areas in which they have made the greatest impact are discussed. Lab-on-a-chip technologies in biomedical research and diagnostics Microfluidics exploits the properties of fluids trapped in submillimetre-scale spaces — the physics behind inkjet printing, DNA microarrays, lab-on-a-chip chemistry and much else — to useful practical effect. In the past decade microfluidic devices have shown considerable promise in diagnostics and primary research in the biological sciences. In this Review, Eric Sackmann, Anna Fulton and David Beebe analyse the progress seen in lab-on-a-chip microtechnologies in recent years and discuss the clinical and research areas in which they have made — and may make — the greatest impact. Microfluidics, a technology characterized by the engineered manipulation of fluids at the submillimetre scale, has shown considerable promise for improving diagnostics and biology research. Certain properties of microfluidic technologies, such as rapid sample processing and the precise control of fluids in an assay, have made them attractive candidates to replace traditional experimental approaches. Here we analyse the progress made by lab-on-a-chip microtechnologies in recent years, and discuss the clinical and research areas in which they have made the greatest impact. We also suggest directions that biologists, engineers and clinicians can take to help this technology live up to its potential.

Circulating Tumor Cells (CTCs) in blood encompass DNA, RNA, and protein biomarkers, but clinical utility is limited by their rarity. To enable tumor epitope-agnostic interrogation of large blood volumes, we developed a high-throughput microfluidic device, depleting hematopoietic cells through high-flow channels and force-amplifying magnetic lenses. Here, we apply this technology to analyze patient-derived leukapheresis products, interrogating a mean blood volume of 5.83 liters from seven patients with metastatic cancer. High CTC yields (mean 10,057 CTCs per patient; range 100 to 58,125) reveal considerable intra-patient heterogeneity. CTC size varies within patients, with 67% overlapping in diameter with WBCs. Paired single-cell DNA and RNA sequencing identifies subclonal patterns of aneuploidy and distinct signaling pathways within CTCs. In prostate cancers, a subpopulation of small aneuploid cells lacking epithelial markers is enriched for neuroendocrine signatures. Pooling of CNV-confirmed CTCs enables whole exome sequencing with high mutant allele fractions. High-throughput CTC enrichment thus enables cell-based liquid biopsy for comprehensive monitoring of cancer. Circulating tumor cells (CTCs) are clinically useful for detecting and monitoring cancer, but they are rare in blood. Here, the authors use a highthroughput microfluidic device to massively enrich CTCs from leukapheresis products to uncover single cell molecular features in prostate and other cancers.

Microfluidic systems are rapidly becoming commonplace tools for high-precision materials synthesis, biochemical sample preparation, and biophysical analysis. Typically, microfluidic systems are constructed in monolithic form by means of microfabrication and, increasingly, by additive techniques. These methods restrict the design and assembly of truly complex systems by placing unnecessary emphasis on complete functional integration of operational elements in a planar environment. Here, we present a solution based on discrete elements that liberates designers to build large-scale microfluidic systems in three dimensions that are modular, diverse, and predictable by simple network analysis techniques. We develop a sample library of standardized components and connectors manufactured using stereolithography. We predict and validate the flow characteristics of these individual components to design and construct a tunable concentration gradient generator with a scalable number of parallel outputs. We show that these systems are rapidly reconfigurable by constructing three variations of a device for generating monodisperse microdroplets in two distinct size regimes and in a high-throughput mode by simple replacement of emulsifier subcircuits. Finally, we demonstrate the capability for active process monitoring by constructing an optical sensing element for detecting water droplets in a fluorocarbon stream and quantifying their size and frequency. By moving away from large-scale integration toward standardized discrete elements, we demonstrate the potential to reduce the practice of designing and assembling complex 3D microfluidic circuits to a methodology comparable to that found in the electronics industry. Significance Microfluidic systems promise to improve the analysis and synthesis of materials, biological or otherwise, by lowering the required volume of fluid samples, offering a tightly controlled fluid-handling environment, and simultaneously integrating various chemical processes. To build these systems, designers depend on microfabrication techniques that restrict them to arranging their designs in two dimensions and completely fabricating their design in a single step. This study introduces modular, reconfigurable components containing fluidic and sensor elements adaptable to many different microfluidic circuits. These elements can be assembled to allow for 3D routing of channels. This assembly approach allows for the application of network analysis techniques like those used in classical electronic circuit design, facilitating the straightforward design of predictable flow systems.

With the ultimate aim to construct a living cell, bottom-up synthetic biology strives to reconstitute cellular phenomena in vitro – disentangled from the complex environment of a cell. Recent work towards this ambitious goal has provided new insights into the mechanisms governing life. With the fast-growing library of functional modules for synthetic cells, their classification and integration become increasingly important. We discuss strategies to reverse-engineer and recombine functional parts for synthetic eukaryotes, mimicking the characteristics of nature’s own prototype. Particularly, we focus on large outer compartments, complex endomembrane systems with organelles, and versatile cytoskeletons as hallmarks of eukaryotic life. Moreover, we identify microfluidics and DNA nanotechnology as two technologies that can integrate these functional modules into sophisticated multifunctional synthetic cells. Bottom-up synthetic biology thrives in reverse-engineering a particular biological function using a minimal set of molecular components, like purified proteins. Recently, precision technologies, like microfluidics, have been used to recombine functional modules towards multifunctional synthetic cells. Synthetic biology can capitalize on a variety of pre-existing on-chip functions, which greatly increases the scope for complexity in the field. Advances in DNA nanotechnology gave rise to a diverse range of fully synthetic functional modules, like DNA-based ion channels or motors, which can replace some protein-based parts. Noteworthy progress has been made in achieving large and stable compartments, organelle-like multicompartment systems, and sophisticated cytoskeletal structures.

Microfluidic devices offer automation and high-throughput screening, and operate at low volumes of consumables. Although microfluidics has the potential to reduce turnaround times and costs for analytical devices, particularly in medical, veterinary, and environmental sciences, this enabling technology has had limited diffusion into consumer products. This article analyzes the microfluidics market, identifies issues, and highlights successful commercialization strategies. Addressing niche markets and establishing compatibility with existing workflows will accelerate market penetration.

Immunoassays have greatly benefited from miniaturization in microfluidic systems. This review, which summarizes developments in microfluidics-based immunoassays since 2000, includes four sections, focusing on the configurations of immunoassays that have been implemented in microfluidics, the main fluid handling modalities that have been used for microfluidic immunoassays, multiplexed immunoassays in microfluidic platforms, and the emergence of label-free detection techniques. The field of microfluidic immunoassays is continuously improving and has great promise for the future.

Miniaturization has been the driving force of scientific and technological advances over recent decades. Recently, flexibility has gained significant interest, particularly in miniaturization approaches for biomedical devices, wearable sensing technologies, and drug delivery. Flexible microfluidics is an emerging area that impacts upon a range of research areas including chemistry, electronics, biology, and medicine. Various materials with flexibility and stretchability have been used in flexible microfluidics. Flexible microchannels allow for strong fluid-structure interactions. Thus, they behave in a different way from rigid microchannels with fluid passing through them. This unique behaviour introduces new characteristics that can be deployed in microfluidic applications and functions such as valving, pumping, mixing, and separation. To date, a specialised review of flexible microfluidics that considers both the fundamentals and applications is missing in the literature. This review aims to provide a comprehensive summary including: (i) Materials used for fabrication of flexible microfluidics, (ii) basics and roles of flexibility on microfluidic functions, (iii) applications of flexible microfluidics in wearable electronics and biology, and (iv) future perspectives of flexible microfluidics. The review provides researchers and engineers with an extensive and updated understanding of the principles and applications of flexible microfluidics.

The natural world provides many examples of multiphase transport and reaction processes that have been optimized by evolution. These phenomena take place at multiple length and time scales and typically include gas–liquid–solid interfaces and capillary phenomena in porous media 1 , 2 . Many biological and living systems have evolved to optimize fluidic transport. However, living things are exceptionally complex and very difficult to replicate 3 – 5 , and human-made microfluidic devices (which are typically planar and enclosed) are highly limited for multiphase process engineering 6 – 8 . Here we introduce the concept of cellular fluidics: a platform of unit-cell-based, three-dimensional structures—enabled by emerging 3D printing methods 9 , 10 —for the deterministic control of multiphase flow, transport and reaction processes. We show that flow in these structures can be ‘programmed’ through architected design of cell type, size and relative density. We demonstrate gas–liquid transport processes such as transpiration and absorption, using evaporative cooling and CO 2 capture as examples. We design and demonstrate preferential liquid and gas transport pathways in three-dimensional cellular fluidic devices with capillary-driven and actively pumped liquid flow, and present examples of selective metallization of pre-programmed patterns. Our results show that the design and fabrication of architected cellular materials, coupled with analytical and numerical predictions of steady-state and dynamic behaviour of multiphase interfaces, provide deterministic control of fluidic transport in three dimensions. Cellular fluidics may transform the design space for spatial and temporal control of multiphase transport and reaction processes. Cellular fluidics provides a platform of unit-cell-based, three-dimensional structures for the deterministic control of multiphase flow, transport and reaction processes.

Droplet-based single-cell RNA-seq has emerged as a powerful technique for massively parallel cellular profiling. While this approach offers the exciting promise to deconvolute cellular heterogeneity in diseased tissues, the lack of cost-effective and user-friendly instrumentation has hindered widespread adoption of droplet microfluidic techniques. To address this, we developed a 3D-printed, low-cost droplet microfluidic control instrument and deploy it in a clinical environment to perform single-cell transcriptome profiling of disaggregated synovial tissue from five rheumatoid arthritis patients. We sequence 20,387 single cells revealing 13 transcriptomically distinct clusters. These encompass an unsupervised draft atlas of the autoimmune infiltrate that contribute to disease biology. Additionally, we identify previously uncharacterized fibroblast subpopulations and discern their spatial location within the synovium. We envision that this instrument will have broad utility in both research and clinical settings, enabling low-cost and routine application of microfluidic techniques. Droplet-based single-cell RNA-seq is a powerful tool for cellular heterogeneity profiling in disease but is limited by instrumentation required. Here the authors develop a 3D printed microfluidic platform for massive parallel sequencing of rheumatoid arthritis tissues.