What is a Lab-On-A-Chip?

Lab-on-a-chip or Micro Total Analysis System (or microTAS) refers to the preparation of samples, biological and chemical reactions, separation and detection in the fields of biology and chemistry, etc. Basic operation unit is integrated or basically integrated on a chip of a few square centimeters, a technology used to complete different biological or chemical reaction processes and analyze its products.

It is through the intersection of analytical chemistry, micro-electro-mechanical processing (MEMS), computers, electronics, materials science and biology, medicine and engineering to achieve chemical analysis and testing, that is, the overall miniaturization, automation, from sample processing to testing, The goal of integration and portability. Recent developments indicate that the development of chip laboratories based on microelectronics processing technology proposed by Manz et al. In the early 1990s will be the same as that of microelectronics technology in the development of information science 40 years ago. It is expected that The chip laboratory will have a similar effect on analytical science and the entire science and technology and related industries in the future development. The computer chip miniaturizes the calculation, and the chip laboratory miniaturizes the laboratory. Therefore, in the field of biomedicine, it can reduce the consumption of precious biological samples and reagents to microliters or even nanoscale upgrades, and the analysis speed is doubled and the cost is Times; in the field of chemistry, it can enable analysis and synthesis that previously required a large number of samples, reagents and a lot of time to complete in a large laboratory, and will spend a small amount of samples and reagents on a small chip in a short time A large number of experiments are completed at the same time; in the field of analytical chemistry, it can make the former large analytical instrument into a square centimeter-scale analyzer, which will greatly save resources and energy. Chip Labs is also a "green" technology because it emits very little pollution.

The chip laboratory or micro-total analysis system was proposed by Manz and Widmer of Ciba-Geigy in Switzerland in 1990. Their initial idea was to develop a miniature device that could be integrated as all the components and operations required for a chemical analysis, emphasizing "micro" and "full". Therefore, & micro; -TAS is regarded as the miniaturization of chemical analysis instruments. Harrison and Manz et al. In 1993

Application in the field of biomedicine

. Clinical blood cell analysis

Recently, Ayliffe et al. Developed the first cell chip analyzer for impedance counting and spectral classification. They combined microfluidics and microelectrodes on the chip to achieve cell classification and counting. Many researchers have since improved this technology, making this technology increasingly perfect, not only for cell classification and counting, but also for quantitative determination of hemoglobin. It is worth mentioning that Gaward has developed a cell analysis chip with a size of 2cm × 3cm. They used impedance and optical analysis techniques to achieve cell analysis and particle size determination. Recently, the University of Washington in the United States and the Backman Company in the United States have developed a disposable plastic chip that can be used to detect blood cells, which has greatly reduced the cost of detection and the size of the instrument.

Nucleic acid analysis

The microfluidic chip laboratory has shown its extremely powerful functions in the field of DNA from the beginning, involving genetic diagnosis, forensic genotyping and sequencing. Tezuka et al. Built an integrated nano-pillar array structure on the chip. This nano-pillar has a diameter of 200-500 nm and a height of 5 m. It is similar to multiple combs arranged together. T4 DNA and 165.5kbp lambda standards have been separated; Lee and others made a disposable microfluidic chip system with integrated micromixer and DNA purification device for DNA sample preparation, and anion exchange resin placed in the microchannel The electrophoretogram of mitochondrial DNA in a single hair filament was obtained; Hofg & auml and others used a microfluidic chip to quickly analyze DNA in cerebrospinal fluid samples, and the time required to diagnose herpes zoster virus encephalitis was only 100% of ordinary gel electrophoresis of cerebrospinal fluid samples One; the author recently used a self-developed microfluidic chip system to analyze PCR samples for the measurement of tumor cell gene methylation. Compared with ordinary gel electrophoresis, the detection sensitivity was increased by 1024 times, and the analysis time was reduced by 100 times. the above.

Protein analysis

Duffy et al. Used a CD disc plastic array chip to perform alkaline phosphatase analysis by centrifugation. Each sample requires only 3L of reagent, and dozens of samples can be analyzed in a few minutes. GYROS in Sweden has produced similar products and performed analysis of myosin, IgG, and IgA. Recently, Burke and Regnier used electrophoretically mediated microanalysis (EMMA) to analyze -galactosidase on the chip. Many researchers, represented by the Ramsey experimental group, use chips to perform two-dimensional electrophoretic separation and detection of proteins and peptides, providing a fast and convenient analysis tool for omics research of proteins.

Drug analysis

Hatch et al. Used the "rapid diffusion immunoassay" method to perform a whole blood Phenyton (an antiepileptic drug) concentration measurement on a chip, without the need to remove red blood cells, and the detection time was less than 20 seconds. Chiem et al. Used competitive immunoassay to measure the concentration of theophylline in the serum sample for the treatment of asthma by mixing unlabeled drug samples with a known amount of fluorescently labeled drugs and drug antibodies, and unlabeled drugs. Competition with labeled drugs leads to a decrease in the peak signal of the labeled drug and antibody complex, while the peak signal of a single labeled drug increases. Using LIF as the detector, the detection limit of the drug in the diluted serum is 1.25 g / L, and the separation time No more than 50 seconds. Sathuluri et al. Used cell chips for high-throughput screening of antitumor drugs. There have been many reports on chiral drug separation and drug interaction research in the chip laboratory.

Small molecule analysis

Argaint et al. Developed a silicon chip containing PO2, PCO2, and pH sensors for blood gas analysis. The size of the entire chip is only 6mm × 22mm. Polyacrylamide and polysilyl chloride polymer layers were used as the internal electrolyte cavity and the gas-permeable membrane, respectively. The entire sensor device is integrated on a silicon chip using an integrated circuit fabrication process. Because the flow channel is also directly integrated on the silicon chip, the amount of samples and reagents is reduced, and the analysis accuracy can meet the needs of clinical testing. This product is suitable for mass production. Koutny et al. Used immunochip electrophoresis to perform chip electrophoresis immunoassay on serum cortisol in a clinically interesting range (10-600 g / L) without the need for preconcentration. Rodriguez et al. Used synchronous cycle mode to separate derivatives of amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine and hydrazone-phenylethylamine in human urine by CZE and MEKC. It is 10mg / L, which is far higher than the requirements of current practical applications. Of course, its application is not limited to the field of biomedicine, it has also been widely used in chemical organic synthesis and analytical chemistry, and will not be described in detail here. ^[1]

Because its development involves many disciplines, and because of the different expertise and interests of researchers, the research focus of the chip laboratory is different, so the diversity of development is reproduced, and the overall development is moving towards a more perfect direction.

1. Chip manufacturing is based on manual micro-electromechanical (MEMS) technology production, which is gradually moving towards the direction of automated, numerically controlled sub-ultraviolet laser direct etching of microchannels.

2. It integrates pumps, valves, pipelines, reactors, etc., and is highly integrated. The most representative work is the Quake research team in the United States [9] integrating more than 3,000 microvalves, 1,000 microreactors, and more than 1,000 microchannels into a silicon material with a size of only a few tens of square millimeters. In this way, the directional flow and distribution of liquids in the interior are completed.

3 The materials used for chip lab manufacturing have come in many styles, and are becoming more and more affordable. From the original expensive glass and silicon wafers, it developed into cheap polymer materials, such as polydimethylsilane (PDMS), polymethyl methacrylate (PMMA), and polycarbonate (PC). Thus, it provides a basis for future single use.

4 Due to the need for the separation and detection of different samples, the modification of the surface of the separation channel shows a diversity of development. Modification can be achieved by sulfonation, nitration, amination, and coupling of bifunctional compounds to the amine groups on the surface; the surface of various molecular components can be obtained; EDA, PDA, CAB, SPH and organosilane and inorganic oxidation The surface of the microchannel is modified by substances to improve the adsorption characteristics, change the hydrophobicity and control the electrodynamic effect to improve the separation efficiency.

5. The driving source of the chip laboratory has developed from electroosmotic flow to hydrodynamics, air pressure, gravity, centrifugal force, shear force and other means. A chip that uses centrifugal force has been commercialized and is called Lab-on-a-CD because the chip is shaped like a small CD disk.

6. The testing technology of the chip laboratory is diversified. Currently the most commonly used detectors are fluorescence and electrochemical detectors. With the development of solid-state electronic devices, some traditional detection methods have also entered this field, such as MIPAES detection using semiconductor microwave sources, SPR detection without labeling, fast impedance spectroscopy (FIS) detection, and NIR time-resolved fluorescence detection.

7. Application direction: The chip laboratory has expanded from the main field of life sciences to other fields. For example, it is used for the analysis and detection of DNA, RNA, protein and other directions. It is also used for the monitoring of chemical and biological reagents and environmental pollution. It monitors microsecond chemical and biochemical reaction kinetics. It is used for the research of many chemical synthesis reactions, drugs and Chemical synthesis and screening. Therefore, the chip laboratory not only opens the door to an infinitely bright tomorrow for not only analytical chemists but also synthetic chemists, especially pharmaceutical synthetic chemists.

8. The industrialization of the chip laboratory is becoming more and more obvious and faster. As its basic research and technical research become more and more specialized and refined, the overall technology development speeds up. In addition, it develops towards detection functionalization, and its application prospects are becoming wider and wider. Therefore, the prospect of industrialization is promising and may become a new economic growth point. ^[1]