Bio-MEMS is an abbreviation for biomedical (or biological) microelectromechanical systems. Bio-MEMS have considerable overlap, and is sometimes considered synonymous, with lab-on-a-chip (LOC) and micro total analysis systems (). Bio-MEMS is typically more focused on mechanical parts and microfabrication technologies made suitable for biological applications. On the other hand, lab-on-a-chip is concerned with miniaturization and integration of laboratory processes and experiments into single (often microfluidic) chips. In this definition, lab-on-a-chip devices do not strictly have biological applications, although most do or are amenable to be adapted for biological purposes. Similarly, micro total analysis systems may not have biological applications in mind, and are usually dedicated to chemical analysis. A broad definition for bio-MEMS can be used to refer to the science and technology of operating at the microscale for biological and biomedical applications, which may or may not include any electronic or mechanical functions. The interdisciplinary nature of bio-MEMS combines material sciences, clinical sciences, medicine, surgery, electrical engineering, mechanical engineering, optical engineering, chemical engineering, and biomedical engineering. Some of its major applications include genomics, proteomics, molecular diagnostics, point-of-care diagnostics, tissue engineering, single cell analysis and implantable microdevices.
History
In 1967, S. B. Carter reported the use of shadow-evaporated palladium islands for cell attachment. After this first bio-MEMS study, subsequent development in the field was slow for around 20 years. In 1985, Unipath Inc. commercialized ClearBlue, a pregnancy test still used today that can be considered the first microfluidic device containing paper and the first microfluidic product to market. In 1990, Andreas Manz and H. Michael Widmer from Ciba-Geigy (now Novartis), Switzerland first coined the term micro total analysis system () in their seminal paper proposing the use of miniaturized total chemical analysis systems for chemical sensing. There have been three major motivating factors behind the concept of . Firstly, drug discovery in the last decades leading up to the 1990s had been limited due to the time and cost of running many chromatographic analyses in parallel on macroscopic equipment. Secondly, the Human Genome Project (HGP), which started in October 1990, created demand for improvements in DNA sequencing capacity. Capillary electrophoresis thus became a focus for chemical and DNA separation. Thirdly, DARPA of the US Department of Defense supported a series of microfluidic research programs in the 1990s after realizing there was a need to develop field-deployable microsystems for the detection of chemical and biological agents that were potential military and terrorist threats. Researchers started to use photolithography equipment for microfabrication of microelectromechanical systems (MEMS) as inherited from the microelectronics industry. At the time, the application of MEMS to biology was limited because this technology was optimized for silicon or glass wafers and used solvent-based photoresists that were not compatible with biological material. In 1993, George M. Whitesides, a Harvard chemist, introduced inexpensive PDMS-based microfabrication and this revolutionized the bio-MEMS field. Since then, the field of bio-MEMS has exploded. Selected major technical achievements during bio-MEMS development of the 1990s include: In 1991, the first oligonucleotide chip was developed In 1998, the first solid microneedles were developed for drug delivery In 1994, the first continuous-flow polymerase chain reaction chip was developed Baier, V.; Bodner, U.; Dillner, U.; Koehler, J.M.; Poser, S.; Schimkat, D.: Miniaturized flow thermocycler, DE-4435107-C1 (1994/09/30; 1996/04/04), US-5716842-A (1994/09/30: 1998/02/10) and chip thermocycling was applied in continuous flow and segmented flow PCR Schneegaß, I.; Bräutigam, R.; Köhler, J.M.: Miniaturized flow-through PCR with different template types in a silicon chip thermocycler, Lab on a Chip 1 (2001), 42-49, DOI: 10.1039/b103846j In 1999, the first demonstration of heterogeneous laminar flows for selective treatment of cells in microchannels Today, hydrogels such as agarose, biocompatible photoresists, and self-assembly are key areas of research in improving bio-MEMS as replacements or complements to PDMS.
Approaches
Materials
Silicon and glass Conventional micromachining techniques such as wet etching, dry etching, deep reactive ion etching, sputtering, anodic bonding, and fusion bonding have been used in bio-MEMS to make flow channels, flow sensors, chemical detectors, separation capillaries, mixers, filters, micropumps and valves. However, there are some drawbacks to using silicon-based devices in biomedical applications such as their high cost and bioincompatibility. Due to being single-use only, larger than their MEMS counterparts, and the requirement of clean room facilities, high material and processing costs make silicon-based bio-MEMS less economically attractive. In vivo, silicon-based bio-MEMS can be readily functionalized to minimize protein adsorption, but the brittleness of silicon remains a major issue.
Plastics and polymers Using plastics and polymers in bio-MEMS is attractive because they can be easily fabricated, compatible with micromachining and rapid prototyping methods, as well as have low cost. Many polymers are also optically transparent and can be integrated into systems that use optical detection techniques such as fluorescence, UV/Vis absorbance, or Raman method. Moreover, many polymers are biologically compatible, chemically inert to solvents, and electrically insulating for applications where strong electrical fields are necessary such as electrophoretic separation. Surface chemistry of polymers can also be modified for specific applications. Specifically, the surface of PDMSs can be ion-irradiated with elements such as magnesium, tantalum, and iron to decrease surface hydrophobicity, allowing for better cell adhesion in in vivo applications. The most common polymers used in bio-MEMS include PMMA, PDMS, OSTEmer and SU-8.
Biological materials
Microscale manipulation and patterning of biological materials such as proteins, cells and tissues have been used in the development of cell-based arrays, microarrays, microfabrication based tissue engineering, and artificial organs. Biological micropatterning can be used for high-throughput single cell analysis,Venkat Chokkalingam, Jurjen Tel, Florian Wimmers, Xin Liu, Sergey Semenov, Julian Thiele, Carl G. Figdor, Wilhelm T.S. Huck, Probing cellular heterogeneity in cytokine-secreting immune cells using droplet-based microfluidics, Lab on a Chip, 13, 4740-4744, 2013, DOI: 10.1039/C3LC50945A, http://pubs.rsc.org/en/content/articlelanding/2013/lc/c3lc50945a#!divAbstract precise control of cellular microenvironment, as well as controlled integration of cells into appropriate multi-cellular architectures to recapitulate in vivo conditions. Photolithography, microcontact printing, selective microfluidic delivery, and self-assembled monolayers are some methods used to pattern biological molecules onto surfaces. Cell micropatterning can be done using microcontact patterning of extracellular matrix proteins, cellular electrophoresis, optical tweezer arrays, dielectrophoresis, and electrochemically active surfaces.
Paper Paper microfluidics (sometimes called lab on paper) is the use of paper substrates in microfabrication to manipulate fluid flow for different applications. Paper microfluidics have been applied in paper electrophoresis and immunoassays, the most notable being the commercialized pregnancy test, ClearBlue. Advantages of using paper for microfluidics and electrophoresis in bio-MEMS include its low cost, biodegradability, and natural wicking action. A severe disadvantage of paper-based microfluidics is the dependency of the rate of wicking on environmental conditions such as temperature and relative humidity. Paper-based analytical devices are particularly attractive for point-of-care diagnostics in developing countries for both the low material cost and emphasis on colorimetric assays which allow medical professionals to easily interpret the results by eye. Compared to traditional microfluidic channels, paper microchannels are accessible for sample introduction (especially forensic-style samples such as body fluids and soil), as well as its natural filtering properties that exclude cell debris, dirt, and other impurities in samples. Paper-based replicas have demonstrated the same effectiveness in performing common microfluidic operations such as hydrodynamic focusing, size-based molecular extraction, micro-mixing, and dilution; the common 96- and 384-well microplates for automated liquid handling and analysis have been reproduced through photolithography on paper to achieve a slimmer profile and lower material cost while maintaining compatibility with conventional microplate readers. Techniques for micropatterning paper include photolithography, laser cutting, ink jet printing, plasma treatment, and wax patterning.
Electrokinetics
Electrokinetics have been exploited in bio-MEMS for separating mixtures of molecules and cells using electrical fields. In electrophoresis, a charged species in a liquid moves under the influence of an applied electric field. Electrophoresis has been used to fractionate small ions, charged organic molecules, proteins, and DNA. Electrophoresis and microfluidics are highly synergistic because it is possible to use higher voltages in microchannels due to faster heat removal. Isoelectric focusing is the separation of proteins, organelles, and cells with different isoelectric points. Isoelectric focusing requires a pH gradient (usually generated with electrodes) perpendicular to the flow direction. Sorting and focusing of the species of interest is achieved because an electrophoretic force causes perpendicular migration until it flows along its respective isoelectric points. Dielectrophoresis is the motion of uncharged particles due to induced polarization from nonuniform electric fields. Dielectrophoresis can be used in bio-MEMS for dielectrophoresis traps, concentrating specific particles at specific points on surfaces, and diverting particles from one flow stream to another for dynamic concentration.
Microfluidics
Microfluidics refers to systems that manipulate small (μL, nL, pL, fL) amounts of fluids on microfabricated substrates. Microfluidic approaches to bio-MEMS confer several advantages:
Flow in microchannels is laminar, which allows selective treatment of cells in microchannels, mathematical modelling of flow patterns and concentrations, as well as quantitative predictions of the biological environment of cells and biochemical reactions Microfluidic features can be fabricated on the cellular scale or smaller, which enables investigation of (sub)cellular phenomena, seeding and sorting of single cells, and recapitulation of physiological parameters Integration of microelectronics, micromechanics, and microoptics onto the same platform allows automated device control, which reduces human error and operation costs Microfluidic technology is relatively economical due to batch fabrication and high-throughput (parallelization and redundancy). This allows the production of disposable or single-use chips for improved ease of use and reduced probability of biological cross contamination, as well as rapid prototyping Microfluidic devices consume much smaller amounts of reagents, can be made to require only a small amount of analytes for chemical detection, require less time for processes and reactions to complete, and produces less waste than conventional macrofluidic devices and experiments