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Microfludics and lab-on-chip technology
Basic concept and historical aspects:
Microfluidic Chip, called Micro Total Analysis Systems (µ -TAS）in Europe or Lab on a Chip in USA, come into being in the twentieth century and served as chip capillary electrophoresis at the beginning. With the co-operation of A. Manz and Harrison in 1992, the capillary electrophoresis separation technique based on micro-fabrication chip was firstly reported [3], thus presented the potential of µ – TAS as a new tool of analytical chemistry. In 2000, G. Whitesides et. al proposed the concept of “soft lithography” for rapid prototyping via fast molding in Polydimethylsiloxane (PDMS)
[4]. The advantage of PDMS based chip is flexible fabrication and low-cost. Quake et al. put forward highly integrated chip with thousands of micro valves and hundreds of micro-reaction chamber in 2002 [5]. This landmark work introduced microfluidic chips from academic world to industry. The relative journal “lab on chip” started in 2001 and lead development of microfluidic chip in the whole world.
A special issue of “lab on a chip” was published in Nature in 2006 to elucidate the history, current situation and prospects of lab on a chip from different points of view [6]. G. M. Whitesides also indicated in the editorial that lab on chip will be the technology of the century. At this point, the strategic significance of lab on chip was identified by academic and industry in higher level and larger scale.
Applications and outlook
Since the 20th century, microfluidic chip has been developed from the laboratory to commercial product application stage in order to meet the needs with measuring and testing, along with various functions of microfluidic products coming into the market. Its application scope has been extended to micro reaction (biological and chemical synthesis), drug transport (micro injection, sustained release, targeted delivery mechanism), industrial and environmental monitoring, analysis processing, pharmaceutical and life science research, disease diagnosis in vitro and the food hygiene inspection, etc. So far, the representative key technologies based on microfluidic chip included three aspects:
(1) Microfluidics-based point of care test (POCT). POCT is defined as medical diagnostic testing that can be performed both in the time and place of direct patient care. This method can provide quick and effective biochemical indicators for each patient, and makes on-site guidance, disease detection, diagnosis and treatment to be a continuous process. The developing trend of POCT is miniaturization, simplicity of operation and fast response with body fluid importing directly. Microfluidic chip incorporation is a top priority for POCT considering the possessed properties of multi units grouped in a controllable platform and scale integration [7].
(2) Ultrahigh throughput screen platform- droplet-based microfluidics. When two insoluble liquids are introduced into the microfluidic chip, micro-droplets can be formed by adjusting the flow speed in the special construction of the channel. These droplets (dispersion phase) can be used as a microreactors or carriers of biochemical samples [8]. The generated droplets can be operated flexibly with homogeneous sizes, altered shapes and excellent heat transfer properties. Single cells could be encapsulated in these microcompartments to measure expression of a reporter gene. Besides, the droplets generation frequency can reach hundreds of KHz, which shows enormous potentiality on high throughput drug screening.
(3) In vitro manipulation platform for mammalian cells- biomimetic laboratory. Microfluidic chip provides micro-channels in the similar dimensions of cells, and the on-chip physical and chemical content can be controlled to match the extracellular microenvironment, thus it can be the most interesting platform for simulating the way that cells work. Cell culture arrays can be achieved in microfluidics for long-term cellular monitoring, and cell analysis can be applied in drug screening, bioinformatics and quantitative cell biology. As shown in figure 1.1.1, there are several steps from on-chip cell culture to cell analysis of interest.
Fig 1.1.1 Micro system cells related experiments, including all the steps in cell analysis [9]. The acoustic functions can be used for the “selection” and “separation” domain.
Chip fabrication with MEMs techniques
Microelectromechanical systems (MEMs) are miniature devices integrating mechanical and electrical components. They are fabricated thanks to integrated circuit (IC) batch processing in size dimension from 1 to 100 μm. MEMs are manufactured by sophisticated manipulations of silicon and other substrates. The micromachining processes could selectively remove parts of the silicon or integrate special structural layers, so as to form mechanical and electromechanical components. Thanks to the electrical properties of silicon, electronics can be integrated close to the sensor, actuator and controller at micro-scale.
MEMs mainly consist of mechanical microstructures, microsensors, microactuators and microelectronics as shown in figure 1.1.2. Microstructures are usually levers, gears, lens and pillars; Microsensors can detect the minimum changes in the environment of mechanical, magnetic, thermal and chemical information. Microactuators can accelerate the physical and chemical reactions in tiny space and also manipulate particles.
Figure 1.1.2 (a) Schematic illustration of MEMS components, (b) SEM image of a dual assembled platform MEMS cap.
Relied on MEMs technology, microelectronics and micromechanical structures are also integrated in microfluidic system enabling interdisciplinary application, and the chip-format scaling of single or multiple lab processes can be implemented. The basis process for most lab- on-chip (LOC) fabrication is photolithography directly derived from microelectronic fabrication. For specific optical characteristics, bio or chemical compatibility, lower production costs and faster prototyping, new processes have been developed such as glass, ceramics and metal etching, deposition and bonding, PDMS process or soft lithography, as well as fast replication methods via electroplating, injection molding and embossing.
In the present microfluidic chips, commonly used materials are silicon, quartz, glass, organic polymer compound, etc. The selecting rules of materials include these aspects:
1. favorable biocompatibility and no reaction with sample; 2. good electrical isolation and heat dissipation; 3. Good optical performance and few disturbances to signal detection; 4. Surface modification can be implemented for electroosmotic flow generation or immobilization of macromolecule; 4. Low-cost and simple process. However, each material has its advantages and disadvantages, and the choice for chip fabrication depends on the chip functions.
Silicon material has favorable thermal stability and chemical inertness. Moreover, there is already mature micromachining technology of silicon. There have been some imperfections in silicon material, that it is not transparent, fragile, high cost, and relative complex processing requirement. For acoustic wave device integrated in lab on chip, silicon substrate is the top choice due to the high speed and low attenuation of sound propagation.
Quartz and glass material can provide good electroosmotic flow and show excellent optical feature, also they can be structured using MEMs techniques such as photolithography and wet etching. For on-chip optical experiments, quartz is still the first choice for chip fabrication. Besides, quartz and glass present hydrophilic
properties so that they are widely used in drop-based microfluidic chips. In recent years, polymer materials are often used in microfluidic chip fabrication. The benefits of relative easy machine shaping and low price are convenient for mass production of disposable microfluidic chips. The representative organic polymers for chip processing are Polydimethylsiloxane (PDMS), Polymethylmethacrylate (PMMA) and Polyurethane (PU). In the cell experiments, PDMS plays an irreplaceable role due to its good air permeability and non-toxicity.
Cell detection in microfluidics and acoustic sensor integration
Cell mechanical properties detection
Cell in vitro studies play an important role in revealing the life phenomenon, disease prevention and disease progression. Cell responses closely related to surround microenvironment, so the similarity between cell growth in local microenvironment and real environment will largely affect their in vitro and in vivo researches. According to the performance, it can be divided into biochemical and biophysical factors. Biochemical factors mainly include the concentration of cytokine (CK) and action of extracellular matrix (ECM); biophysical factors mainly include the extracellular matrix materials hardness, density and porosity, as well as some mechanical force.
Dynamic balance in cell microenvironment is a significant condition for normal cell proliferation, differentiation and metabolism [10]. The mechanical property of cell is one factor which influences the environment change. Among them, the cell- substrate adhesion is an essential process for survival, differentiation, and migration of many types of cells. In this process, a cell experiences the contact with the substrate, loose attachment and the spread of its membrane over the substrate surface can be studied. By means of restructuring, the cell-substrate adhesion plays a fundamental role in regulating migration, proliferation, and differentiation of cells [11].
Microfluidic chips are particularly suitable for cell study, because the dimensions of microchannels are matched with cell size and liquid control can be precisely realized. Microfluidic chip can also mimic the vasculature in vivo to transmit cell medium, interstitial fluid and cellular metabolism. Moreover the biochemical and physical parameters can be adjusted for on-chip cell culture. In addition, with the integration of micro sensors and actuators, various functions can be achieved such as buffer mixing, transfer, separation and capture.
Acoustic detection in lab-on-chip
Acoustic method has been widely developed in biology and medicine. The famous applications in commercialization are scanning acoustic microscope and ultrasonography. The core components are ultrasonic transducers using piezoelectric effect for acoustic beam generation. The acoustic technique can implement a gentle way to biological samples in a non- contact mode and reveal their internal structures. In another aspect, the transducers can be fabricated in the microdevice and the acoustic energy can be guided within the microchannel fabricated by MEMs technology. This property has paved the way for the acoustic modulus integrated in the lab-on-chip field. The miniaturization and high integration of acoustic modulus into a small chip show the promising solutions that meet the requirement of the Point-of-care testing (POCT) [12]. The analyte types include proteins, cells, nucleic acids, and metabolites.
The commercialized acoustic sensors in medicine are ultrasound probes based devices, including ultrasonography [13], d-mode ultrasonic diagnostic apparatus [14] and scanning acoustic microscopy [15]. The acoustic modulus is also integrated in microfluidics for biosensing applications. Current study mainly demonstrates two types of acoustic devices: Bulk acoustic wave (BAW) based quartz crystal microbalances (QCM) sensors and surface acoustic waves (SAW) based sensors. Here we focus on introducing the acoustic devices for on-chip applications, meanwhile, the scanning acoustic microscopy technology is discussed which is waiting to be integrated into lab-on-chip.
Table of contents :
Abstract
Acknowledgements
Abbreviations
General instruction of the thesis
Chapter 1: Introduction to lab lab-on -chip
1.1 Microfluidics and lab lab-on -chip technology
1.1.1 Basic concept and historical aspects aspects
1.1.2 Applications and outlook outlook
1.1.3 Chip fabrication with MEMs techniques
1.2 Cell detection in microfluidics and acoustic sensor integration integration
1.2.1 Cell mechanical properties detection
1.2.2 Acoustic detection in lab lab-on -chip
1.3 Microfluidic approaches of cell manipulation
1.3.1 Cell manipulation significance
1.3.2 Passive manipulation
1.3.3 Active manipulation
1.3.4 Magnetic manipulation for CTCs detection
1.4 Acousti c manipulation in microfluidics systemssystems
1.4.1 Bulk standing wave manipulation in lab on chip chip
1.4.2 Surface standing acoustic wave method method
1.4.3 Traveling wave s inducing acoustic streaming
1.5 Acoustic tweezers development in micro micro-systemsystem
1.5.1 Concept of acoustic tweezerstweezers
1.5.2 Single beam acoustic tweezers (SBAT) SBAT)
1.5.3 On -chip high frequency acoustic characterization characterization
1.6 Conclusion and p erspective
References
Chapter2: Technological development and acoustic reflection enhancement enhancement
2.1 Introduction of the problems and improvements
2.2 45˚ mirrors fabrication and improvementimprovement
2. 2.1 45 ˚ plane wet etch in silicon silicon
2. 2.2 45˚ mirrors fabrication improvement improvement
2. 3 acoustic reflection and optimization
2. 3.1 Acoustic wave reflection on solid solid-air interface interface
2. 3.2 Coating layer calculation
2. 4 Microicro-system design and fabrication
2.4.1 Improved structure: 1 vertical mirror system and single lens system
2. 4.2 Microchannel fabricated by dry etch
2. 4.3 Gold deposition on mirrors and vertical channels channels
2.5 Piezoelectric transducer fabrication and characteristics
2.5.1 Piezo
2.5.1 Piezo-electric material choiceelectric material choice
2.5.2 Thick ZnO film deposit
2.5.2 Thick ZnO film deposit
2.5.3 Ground and top electrodes optimization
2.5.3 Ground and top electrodes optimization
2.6 PDMS PDMS bondingbonding for device packagefor device package
2.7 Summaryummary and discussionand discussion
Appendix: main technology in our fabrication
Appendix: main technology in our fabrication
References
Chapter3: LabLab-on -chip high frequencychip high frequency acoustic coustic detectiondetection and manipulationand manipulation
3.1 Acoustic wave characterization
3.1 Acoustic wave characterization
3.1.1 Signal processing and method
3.1.1 Signal processing and method
3.1.2 Experimental set up
3.1.2 Experimental set up
3.2 Acoustic waveguiding characterization and reduction of Acoustic waveguiding characterization and reduction of mode conversionmode conversion…
3.2.1 Acoustic reflection on 45
3.2.1 Acoustic reflection on 45˚ mirrorsmirrors
3.2.2 Comparison of 45° mirrors coating layers performances
3. 3 Acoustic characterization in microfluidic channelAcoustic characterization in microfluidic channel
3. 3.1 .1 Waveguiding with vertical Waveguiding with vertical mirrorsmirrors
3. 3.2 Liquid characterization with water and KI solutionLiquid characterization with water and KI solution
3.3.3 Particles detection in the microchannel
3.3.3 Particles detection in the microchannel
3.4 Acoustic lens integration
3.4.1 Lens design and characte
3.4.2 Particles detection using acoustic lenses
3.5 On-chipchip temperature measurement using acoustic wavetemperature measurement using acoustic wave
3.5.1 Methods for on
3.5.2 Temperature characterization in the channelization in the channel
3.6 Acoustic manipulation in microfluidic channels
3.6 Acoustic manipulation in microfluidic channels
3.6.1 Force analysis experienced by particles in the acoustic field
3.6.2 Manipulatanipulate particlese particles in microchannels
3.6.3 Loss evaluation of the chip and matching design
3.7 Summarummary and outlooky and outlook
Reference
Conclusions and perspectives
