High-density microfluidic chips contain plumbing networks with thousands of micromechanical valves and hundreds of individually addressable chambers. These fluidic devices are analogous to electronic integrated circuits fabricated using large scale integration (LSI). A component of these networks is the fluidic multiplexor, which is a combinatorial array of binary valve patterns that exponentially increases the processing power of a network by allowing complex fluid manipulations with a minimal number of inputs. These integrated microfluidic networks can be used to construct a variety of highly complex microfluidic devices, for example the microfluidic analog of a comparator array, and a microfluidic memory storage device resembling electronic random access memories.

https://science.sciencemag.org/content/sci/298/5593/580.full.pdf

Microfluidic large scale integration

After having reviewed some aspects of microfluidic system preparation in the first part (1), in this second part of the review we will cover a number of standard operations (namely: sample preparation, sample injection, sample manipulation, reaction, separation, and detection) as well as some biological applications of micro total analysis systems (namely: cell culture, polymerase chain reaction, DNA separation, DNA sequencing, and clinical diagnostics). As previously, we will include papers issued from different scientific journals as well as useful abstracts from three conference proceedings: MEMS, Transducers, and μTAS. In this second part, we do not include the period covered by the history section (1975-1997) from part 1 but try to cover the relevant examples of the literature published between January 1998 and March 2002. We briefly describe articles that struck us as needing special attention, while more “standard” papers are dutifully reported in groups of interest. An article might be included in more than one section, depending on the ideas developed in it.

Micro total analysis systems. 2. Analytical standard operations and applications.

Polymer microfluidic devices

The invention provides systems, including apparatus, methods, and kits, for the microfluidic manipulation and/or detection of particles, such as cells and/or beads. The invention provides systems, including apparatus, methods, and kits, for the microfluidic manipulation and/or analysis of particles, such as cells, viruses, organelles, beads, and/or vesicles. The invention also provides microfluidic mechanisms for carrying out these manipulations and analyses. These mechanisms may enable controlled input, movement/positioning, retention/localization, treatment, measurement, release, and/or output of particles. Furthermore, these mechanisms may be combined in any suitable order and/or employed for any suitable number of times within a system. Accordingly, these combinations may allow particles to be sorted, cultured, mixed, treated, and/or assayed, among others, as single particles, mixed groups of particles, arrays of particles, heterogeneous particle sets, and/or homogeneous particle sets, among others, in series and/or in parallel. In addition, these combinations may enable microfluidic systems to be reused. Furthermore, these combinations may allow the response of particles to treatment to be measured on a shorter time scale than was previously possible. Therefore, systems of the invention may allow a broad range of cell and particle assays, such as drug screens, cell characterizations, research studies, and/or clinical analyses, among others, to be scaled down to microfluidic size. Such scaled-down assays may use less sample and reagent, may be less labor intensive, and/or may be more informative than comparable macrofluidic assays.

Microfluidic particle-analysis systems

A novel electrokinetic instability (EKI) micromixer and method takes advantage of the EKI to effect active rapid stirring of confluent microstreams of biomolecules without moving parts or complex microfabrication processes. The EKI is induced using an alternating current (A/C) electric field. Within seconds, the randomly fluctuating, three-dimensional velocity field created by the EKI rapidly and effectively stirs an initially heterogeneous solution and generates a homogeneous solution that is useful in a variety of biochemical and bioanalytical systems. Microfabricated on a glass substrate, the inventive EKI micromixer can be easily and advantageously integrated in molecular diagnostics apparatuses and systems, such as a chip-based “Lab-on-a-Chip” microfluidic device.

Electrokinetic instability micromixer

A channel-cell system is provided for detecting the presence and/or measuring the presence of analyte particles in a sample stream comprising a laminar flow channel (100), two inlet means (30, 20) in fluid connection with said laminar flow channel (100) for respectively conducting into the laminar flow channel (100) an indicator stream (70) which may comprise an indicator substance which indicates the presence of said analyte particles by a detectable change in property when contacted with said analyte particles, and the sample stream (80), wherein the laminar flow channel (100) has a depth sufficiently small to allow laminar flow of the streams and a length sufficient to allow particles of the analyte to diffuse into said indicator stream (70) to the substantial exclusion of said larger particles in the sample stream (80) to form a detection area; and outlet means (60) for conducting the streams out of the laminar flow channel (100) to form a single mixed stream.

Microfabricated diffusion-based chemical sensor

A reference T-sensor system is provided for detecting the presence and/or measuring the concentration of analyte particles in a sample stream comprising a laminar flow channel (100), three or more inlet means (40, 50, 55) in fluid connection with the laminar flow channel (100) for respectively conducting into the laminar flow channel an indicator stream (70) which may comprise an indicator substance which indicates the presence of the analyte particles by a detectable change in property when contacted with analyte particles, the sample stream (80), and a reference stream (75), which can be either a control stream or an internal standard stream or both.

Simultaneous analyte determination and reference balancing in reference T-sensor devices

This invention provides microfabricated systems for extraction of desired particles from a sample stream containing desired and undesired particles. The sample stream is placed in laminar flow contact with an extraction stream under conditions in which inertial effects are negligible. The contact between the two streams is maintained for a sufficient period of time to allow differential transport of the desired particles from the sample stream into the extraction stream. In a preferred embodiment the differential transport mechanism is diffusion. The extraction system of this invention coupled to a microfabricated diffusion-based mixing device and/or sensing means allows picoliter quantities of fluid to be processed or analyzed on devices no larger than silicon wafers. Such diffusion-based mixing or sensing devices are preferably channel cell systems for detecting the presence and/or measuring the quantity of analyte particles in a sample stream.

Microfabricated devices and methods

This invention provides a method and apparatus for detecting the presence of analyte particles in a sample fluid also comprising larger particles, particularly blood. It exploits diffusion to provide simultaneous filtering of the larger particles and reaction of the analyte particles. A sample stream and a reagent stream join on the upstream end of a laminar flow reaction channel and flow in adjacent laminar streams. The reagents can be in solution or immobilized on a bead. The analyte particles diffuse from the sample stream into the reagent stream, leaving behind the larger particles in the residual sample stream. In the reagent stream the analyte particles react with reagent particles and form product particles, thereby creating a product stream. At the downstream end of the reaction channel, the residual sample stream and the product stream are divided. The product particles are then detected, preferably optically, in the product stream. Prior to detection, the product stream can undergo further filtering or separation, or can join a second reagent stream to form secondary product particles. This apparatus and method can be used to implement competitive immunoassays or sandwich immunoassays using enzymatically or fluoroscently labeled immunoreagents. The apparatus and method can also be used to synthesize products, in which case two reagent streams join in the laminar flow reaction channel.

Simultaneous particle separation and chemical reaction

Microfluidic laminate-based structures incorporating hydrodynamic focusing and flow channels with dimensions much less than 1 mm were fabricated and used to transport and analyze blood samples. Optically transparent windows integral to the flow channels were used to intercept the sample streams with a tightly focused diode laser probe beam. The size and structure of the blood cells passing through the laser beam determined the intensity and directional distribution of the scattered light generated. Forward and small angle light scattering channels were used to count and differentiate platelets, red blood cells, and various populations of white blood cells. All the blood samples used were characterized using a commercial hematology analyzer for comparison and validation purposes.

Caicai Wu

Papers

Microfabricated diffusion-based chemical sensor

Simultaneous analyte determination and reference balancing in reference T-sensor devices

Microfabricated devices and methods

Simultaneous particle separation and chemical reaction

Results Obtained using A Prototype Microfluidics-Based Hematology Analyzer