Chip-based miniaturization

Weissenstein U, Schneider MJ, Pawlak M, Cicenas J, Eppenberger-Castori S, Oroszlan P, Ehret S, Geurts-Moespot A, Sweep FCGJ, Eppenberger U (2006) Protein chip based miniaturized assay for simultaneous quantitative monitoring of cancer biomarkers in tissue extracts. Proteomics 6 1427-1436... 

Micro Total Analysis Systems (pTAS) are chip-based micro-channel systems that serve for complete analytics. The word Total refers to the monolithic system character of the devices, integrating a multitude of miniature functional elements with minimal dead volumes. The main fields of application are related to biology, pharmacology, and analytical chemistry. Detailed applications of pTAS systems are given in Section 1.9.8. Recently, pTAS developments have strongly influenced the performance of organic syntheses by micro flow (see, e.g., [29]). By this, an overlap with the micro-reactor world was made, which probably will increase more and more. 

Either the information obtained during the data-dependent acquisition is sufficient or a fraction of interest can be re-analyzed by chip-based infusion at a flow rate ca. 200 nl min. Due to the miniaturization sample consumption is very low (typically 1-3 pi) and acquisition time is no longer critical. Therefore various MS experiments can be performed on various instruments, including MS and accurate mass measurements. An additional advantage is that the eluent can be removed and the infusion solvent can be optimized for positive or negative ion detection or for deuterium exchange measurements. 

Miniaturizing a conventional-flow screening system (macro-scale system) to a chip-based system comprises a number of changes, such as flow rates, reagent supply, and the material. While the conventional system with the open tubular reactors is restricted to polymer reactors, the choice of materials for the chip is... 

Although this section provides a brief description of most commonly nsed detectors for HPLC, most of the focus is on a few detection modes. Optical absorbance detectors remain the most widely nsed for HPLC, and are discnssed in some detail. We also focns on flnorescence, condnctivity, and electrochemical detection, as these methods were not widely nsed for HPLC in the past, bnt are especially well suited to micro- and nano-flow instrnments becanse of their high sensitivity in small sample volumes. Mass spectrometry has also come into wide and rontine nse in the last decade, but as it is the subject of another chapter, it will not be fnrther discnssed here. Miniaturization has been particularly important for capillary and chip-based electrophoresis, which often employs sub-nanoliter detection volnmes [36,37]. 

Miniaturized LC/MS formats based on micromachined chip-based electrospray emitters and ionization sources on silicon (Schultz et al., 2000 Licklider et al., 2000 Ramsey and Ramsey 1997 Xue et al., 1997) and plastic (Vrouwe et al., 2000 Yuan and Shiea, 2001, Tang et al., 2001) microchips is a proactive approach for scale-down platforms. Various micromachining processes are used to fabricate these devices. These microanalytical technologies would create integrated sample preparation and LC/MS applications. The potential benefits of such a system include reduced consumption of sample/reagents, low cost, and disposability. 

As in the SLM systems, FS- and HF-MMLLE configurations can be run automatically in flowing modes and operated off-line or connected on-line to analytical instruments. Recently, a microfluidic chip-based FS-MMLLE system was reported.83 In addition, miniaturized, nonautomated, nonflowing, off-line MMLLE systems are usually used with HF membranes. The emphasis in this section will be placed on these latter modes of MMLLE operation. 

The first two points represent a general motivation for miniaturization in separation science independent of the actual fabrication technology. The benefit of a reduction of the consumption of sample, reagents, and mobile phase in chemical and biochemical analysis is self-evident and does not need to be discussed further (reduced consumption of precious samples and reagents, reduced amounts of waste, environmental aspects). This advantage is, however, sharply contrasted by its severe implications on the detection side, as discussed elsewhere in this volume in detail. The detection of the separated zones of very small sample volumes critically depends on the availability of highly sensitive detection methods. It is not surprising that extremely sensitive laser-induced-fluorescence (LIF) has been the mostly used detection principle for chip-based separation systems so far. 

Electrochemical detection offers also great promise for CZE microchips, and for other chip-based analytical microsystems (e.g., Lab-on-a-Chip) discussed in Section 6.3 (77-83). Particularly attractive for such microfluidic devices are the high sensitivity of electrochemical detection, its inherent miniaturization of both the detector and control instrumentation, low cost, low power demands, and compatibility with micromachining technologies. Various detector configurations, based on different capillary/working-electrode... 

Recent breakthroughs in miniaturized analytical instrumentation include fully integrated lab-on-a-chip and micro total analysis systems. The former have had only moderate success as many analytical chemists have been reluctant to accept them [67]. At present, chip-based analytical systems are subject to major shortcomings such as the risk of analyte adsorption on walls and at interfaces — which is important especially in low-volume analytical systems — and optical interference at the walls of the chips hampering detection. Further research in this field is required in order to effectively circumvent these shortcomings [68]. 

Levitation of small amounts of sample can be used to avoid contact with solid walls around the sample in a gas-surrounding medium (air in most cases). Levitation provides advantages similar to those of miniaturization in chip-based methods (basically, low reagent and sample consumption). In addition, levitation avoids contamination between samples and external objects, and also adverse effects of sample-wall contact on detection [69]. 

Caliper Technologies Corporation, Palo Alto, California, is working toward creating a miniature chemistry laboratory about the size of a toaster that can be used with plug-in chip-based laboratories. Various chips would be furnished with the unit that would be appropriate for different types of analyses. The entire unit would be connected to a computer to collect and analyze the data. There is even the possibility that these laboratories could be used in the home to perform analyses such as blood sugar and blood cholesterol and to check for the presence of bacteria such as E. coli and many others. This would revolutionize the health care industry. ... 

However, to realize a practical and cost-effective system for biomedical applications, a microvalve system that will process human whole blood is essential. To date, most microvalve systems have been microfabricated from silicon, although valves using plastic membranes have also been developed. Chip-based microvalve systems have been classified as either active microvalves (with an actuator) or passive (check) microvalves (without an actuator). The miniaturization of the active microvalve systems is restricted by the size of the actuator. 

When compared to the analysis of hybridization events by detecting labels -even on arrays, the DNA MassARRAY approach differs significantly. The MassEXTEND assay is designed to give only the relevant information. The mass spec-trometric approach enables a direct analyte detection with 100% specificity and needs no redundancy. This accuracy and efficacy is combined with sample miniaturization, bioinformatics and chip-based technologies for parallel processing of numerous samples. 

Abstract. Microfluidics is key to miniaturize bio-chemical and biomedical methods and processes into chip based technology. Basics of electrokinetic microfluidics will be reviewed first. Three types of lab-on-a-chip devices, PCR lab-on-a-chip, flow cytometer lab-on-a-chip and immunoassay lab-on-a-chip are discussed here. The working principle, key microfluidic processes and the current status of these lab-on-a-chip devices are reviewed. 

The approach to use chip based electroanalytical systems to monitor the dynamics of processes in living cells facilitate the possibility to integrate the detection systems to microfluidic cell culture chips. In virtue of the functional principle of such systems, cells can be cultured on the platform where detection takes place. Hence, the measurements can be conducted in an environment that has been tailor-made for proper adaptation to the requirements of the cultured cells. Furthermore, such miniaturized systems possess the capability to achieve operational automation and facilitate measurements... 

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