Micro total analysis systems: fundamental advances and biological applications.

It has been more than 20 years since the first micro total analysis systems (μTAS) papers were published. Initial reports of these devices, which are also commonly referred to as Labs-on-a-Chip (LOC), LabChips, microchips or microfluidic devices, generally focused on separations and the development of a variety of functional elements for sample manipulation and handling. One of the greatest potentials of μTAS, however, has always been in the integration of multiple functional elements to produce truly sample-in/answer-out systems. In the last decade, the march toward developing such integrated devices has accelerated significantly. Many μTAS reported now are quite sophisticated with multiple sample handling and processing steps that are highly integrated and often automated. While most of these devices are not yet strictly sample-in/answer-out several come quite close. There are, however, some significant hurdles still facing the development of true sample-in/answer-out systems especially in the areas of sample preparation, chip-to-real-world interfacing and detection. Additionally, further progress is needed in the miniaturization or elimination of external fluidic control elements. μTAS have found a major niche in the areas of biological and biomedical analyses, especially cellular and nucleic acid analysis. This focus on biological applications reflects the capabilities of these devices to precisely and accurately handle picoliter volumes of materials and to integrate cell transport, culturing or trapping with reagent delivery, and on-chip detection. Significant progress has been made in the development of a variety of cellular analysis systems; this field, however, is still rapidly growing and many papers focused on the expansion of such capabilities continue to be seen. Areas of focus remain the development of substrate materials and culturing conditions that do not unnaturally perturb or stress cells and that allow for extended culturing so that changes in cell physiology over time can be monitored. In addition, a significant amount of work has been directed to developing cell co-cultures on μTAS to mimic tissues, organs, and organ systems. μTAS can create unique, controlled environments to study cell-cell interactions that can not be replicated in any other way. For cellular assays substantial increases in throughput are also a focus. While significant development toward completely integrated cell assays has occurred and even some clinical demonstrations of such assays have been reported, the availability of commercial, fully integrated devices, however, has lagged. In addition to biological assays, the creative expansion of the basic μTAS toolkit with centrifugal platforms, digital microfluidics, and paper-based devices has substantially expanded its potential application base. Interest in these devices is generally more clinical in nature and again focused on generating sample-in/answer-out analyses. Significant work, however, is still needed for most of these platforms in terms of substrate materials, fluid control, sample handling, integration and throughput. Finally, the development of label-free detection technologies remains of interest. This review focuses on recent advances in μTAS technology in the areas of integrated biological assays and diagnostics with an analytical focus. We have also tried to highlight some material, fabrication, coating, separation, and detection advances with more general applicability. We have not included, for the most part, papers on synthesis, biosensors, theory, simulations or reviews. The papers included in this review were published between September 2012 and September 2013. The material was compiled using several strategies including extensive searches using Scifinder, Web of Science, PubMed, and Google Scholar. The contents of high impact journals were also scanned, including Analytical Chemistry, Lab-on-a-Chip, Nature, PNS, Appl. Phys., Letters, and Langmuir. Almost 2000 papers relating in some way to microfluidics were examined. We have done our best to try to identify some of the most interesting and promising papers and to report on them in this review. Without a doubt we have missed a few excellent papers and had to eliminate others based on space constraints and readability. For those papers that we have failed to include, we apologize in advance and welcome comments regarding any oversight that we have made.