What are the materials used for manufacturing microfluidic chips? What are the advantages and limitations of each material? How can composite substrates provide extra features? We answer these questions in the following review.
A microfluidic chip is a pattern of molded or engraved microchannels. Output holes are built through the chip and serve as links between the microchannels network and the macro-environment. Presenting valves for active flow control, microfluidic chips can easily handle fluids no matter the area of application.
Depending on the desired application (lab-on-a-chip, detection of pathogens, electrophoresis, DNA analysis, etc), the microchannels network design must be adapted to meet the requirements to deliver the coveted results. Thus, the materials employed for microfluidic chips should also be adequate with appropriate properties.
Silicon and glass were first used for microfluidic applications, however as time passed and technological advances occurred, new materials including polymer, paper substrates, and composites were used. In research, device versatility and performance are prioritized, whereas, in commercialization, production cost, reliability, and ease of use are placed above all. Moreover, each material has specific microfabrication strategies and provides certain device properties. Therefore, the material used for making microfluidic chips plays an important role in microfluidic technologies.
These materials can be classified as inorganic, polymeric, paper, hydrogels, and composites. This review mainly focuses on their properties for the fabrication of microfluidic chips. We recommend reading the interesting review by Nielsen et al. [1].
The first material used for microfluidics was silicon even though it was quickly replaced by glass and then polymers. Silicon was first selected due to its resistance to organic solvents, ease of metal depositing, high thermo-conductivity, and stable electroosmotic mobility. However, this material is not easy to handle owing to its hardness which doesn’t make it easy to create active microfluidic components such as valves and pumps. Dangerous chemicals used during the fabrication process also require protective facilities [2].
Transparent to infrared, silicon is an opaque material, thus fluorescence detection or fluid imaging is difficult to perform. This issue can be easily overcome by grafting silicon to transparent materials such as polymers or glass in an attempt to get a hybrid system ready to be used [3]. Silicon surface chemistry is based on the silanol group (−Si−OH), so using a chemical modification of silicon surface could be a way to reduce non-specific adsorption or improve cellular growth for instance.
Its elastic modulus is quite high (130−180 GPa) and devices using silicon are fabricated through wet/dry etching or additive methods such as metal or chemical vapor deposition [1]. Droplet-based polymerase chain reaction (PCR) or nanowires for label-free cardiac biomarker detection are possible applications for silicon microfluidic chips.
After the initial focus on silicon, glass was the material selected to build microfluidic chips. Optically transparent and electrically insulating, glass is an amorphous material. This material is generally processed with standard photolithography or wet/dry etching methods [2].
Glass is compatible with biological samples, it is also a material not permeable to gas and has relatively low non-specific adsorption [4]. Because gas can go through glass chips that generally present enclosed channels and chambers, this material cannot be used for long-term cell culture.
Glass capillaries were already used for gas chromatography, and capillary electrophoresis (CE) microchannels before integrating the microfluidic field [5].
Other typical applications of glass microfluidic chips include on-chip reactions, droplet formation, solvent extraction, and in situ fabrication [1]. Finally, due to its high thermo-conductivity and stable electroosmotic mobility on its surface, a microchannel made of glass provides better performance than other materials.
Just like silicon, glass modification chemistry is silanol-based. Similarly, due to its hardness and the high fabrication cost, many limits to glass applications in microfluidics arise (protective facilities, super clean environment for bonding, high temperature and pressure required in the fabrication process, etc). These limitations are the origin of the development of alternative low-cost chip materials that can be easily fabricated and are compatible with broader biological applications [6].
Microfluidic devices made from ceramic generally use low-temperature cofired ceramic (LTCC). This ceramic is an aluminum oxide-based material that comes in laminate sheets that are patterned, assembled, and then heated at elevated temperatures [4].
The LTCC technology is well-established for low-volume, high-performance, high-volume, low-cost, and portable wireless applications. It has good electrical and mechanical properties, high reliability, and low non-specific adsorption [7].
The advantages of the LTCC structure are a much lower price and a shorter development time. LTCC technology also allows the integration of heaters, sensors, and electronics (control and measurement electronics, and a light detection system) into one module. It is the main advantage of this technology over silicon, glass, and polymer technologies [8].
Thick film materials offer the possibility of manufacturing not only a network of conductive paths in a package but also other electronic components, sensors, and microsystems.
Polymer-based chips were introduced several years after silicon/glass chips. The vast variety of polymers grants great suitable materials with specific properties. Polymers are easy to access and inexpensive compared to inorganic materials, they are now the most commonly used microchip materials [1]. According to their physical properties, polymers can be classified into elastomers and thermoplastics.
Elastomers consist of cross-linked polymer chains that are normally entangled; they can stretch or compress when an external force is exerted, and return to the original shape when the external force is withdrawn. They present weak inter-molecular forces and most of the time they have a low Young’s modulus and high failure strain compared to other materials [9].
Polydimethylsiloxane (PDMS) has been widely used in microfluidics for rapid prototyping because it is easy to fabricate, bonds strongly to glass and ceramic, and has good optical transparency and elastomeric properties [8].
PDMS is the most common microfluidic material used in research laboratories due to its reasonable cost, rapid fabrication, and ease of implementation. Device molds are formed via conventional machining or photolithography methods, and PDMS microstructures are cast and cured on these molds [9].
PDMS has a low elastic modulus (300−500 kPa), making it suitable for valve and pump fabrication. Its gas permeability can be advantageous for oxygen and carbon dioxide transport in cellular studies, however, bubble formation can be problematic. PDMS is susceptible to nonspecific adsorption where proteins and hydrophobic analytes in the medium may attach to the free hydrophobic sites of the PDMS.
Chemical modification of PDMS can address these issues, plasma exposure will hydrophilize the exposed PDMS surface. However, after this treatment, the newly formed hydrophilic surface is not stable and can be reverted to its original hydrophobic form shortly after [10]. The tendency for absorbing and dissolving hydrophobic molecules that cause swelling when in contact with non-polar solvents is also one of the consequences of PDMS hydrophobic surface.
Insoluble and highly resistant to creep, thermosets are polymers with chains irreversibly bound together when cross-linked. They are easy and fast to craft polymers that are optically transparent and inexpensive. They don’t melt, don’t swell with certain solvents and they are not gas permeable, which makes them inadequate material to use for long-term cell cultures [11].
Their high mechanical and physical strength is due to a highly cross-linked polymeric structure, and they harden when heated. One major advantage of thermosets is for 3D microfabrication using photopolymerization. Thermosets are improper for the fabrication of valves due to their high stiffness, and with their high cost, their applications in microfluidics are limited [11].
Thermoset polyester (TPE) is one of the most used thermosets in microfluidics. It is a transparent material in the visible and has a higher elastic modulus (1−100 MPa) than PDMS but a lower one than typical thermoset plastics (>1 GPa). TPE is formed by the polymerization of polyester and styrene through UV or heat. This hydrophobic material requires surface modification through buffer additives or chemical reactions allowing water to flow through microfluidic channels. TPE was proposed in microfluidics as an alternative material to PDMS providing better chemical and solvent compatibility [12].
Thermoplastics are materials that can be remolded multiple times by reaching glass transition temperature (Tg). They are highly crosslinked polymers that can retain their shape after cooling, and they are also suitable for micro-machining processes. Optically transparent polymers, thermoplastics are resistant to the permeation of small molecules, and stiffer than elastomers. Barely permeable to gas, their sealed microchannels are unsuitable for long-term cell cultures. Plus, thermoplastic valves are difficult to make because of their rigidity [13].
Thermoplastics are fabricated by thermomolding, a process requiring templates in metal or silicon for use at high temperatures. It allows the production of thousands of replicas at a high rate and low cost and is excellent for commercial production but not economical for prototypic use.
Unfortunately, thermoplastics cannot form conformal contact with other surfaces, unlike PDMS. Their surface can be modified by dynamic coating or surface grafting depending on their applications. Covalent-modified surfaces are generally more stable for thermoplastics than PDMS. For example, it is possible to easily integrate electrodes for flexible circuits, and thermoplastic surfaces can retain hydrophilicity for up to a few years after treatment with oxygen plasma [13].
Polystyrene (PS) is optically transparent, biocompatible, inert, and rigid. Its hydrophobic surface can be made hydrophilic by various physical and chemical means including corona discharge, gas plasma, and irradiation. However, the necessity of expensive equipment required to realize complex chips from such polymer (injection molding, hot embossing) could be a hindrance to its use. PS is adapted to mass manufacturing processes, thus it could facilitate the translation of the currently used manufacturing process to microscale systems [14].
Some PS microfluidic chips (prototypes) take advantage of the shrinkage properties of thermoplastic PS sheets. In fact, after heating, etched microfluidic channels become thinner and deeper than the tooling. Faster than soft lithography, this technique includes a simultaneous rapid bonding step. PS is the most commonly used material in cell culture mainly due to its commercial availability and interesting price [15].
Due to its popularity in this field, cell culture on a microfluidic chip (organ-on-a-chip) can be a potential application. It is possible to modify the PS surface to enable cell adhesion and growth while also preventing bubble formation, and to that extent, the material can be treated with oxygen plasma before bonding. However, plasma treatment can modify bond strength by altering the chemical composition of PS surface. Another method could consist of pre-coating microchannels with extracellular matrix proteins before cell seeding, to promote cell adhesion [15].
Polycarbonate (PCB) is a durable material created by the polymerization of bisphenol A and phosgene, resulting in repeating carbonate groups. PCB is suited for DNA thermal cycling applications due to its transparency in the visible and its very high glass transition temperature (∼145 °C). The other advantages of PCB are its low cost, high impact resistance, low moisture absorption, and good machining properties. However, PCB includes poor resistance to certain organic solvents and absorbance in UV [14].
As previously mentioned, PCB is the material of choice for a range of microfluidic applications in biomedical studies and bioanalyses that include polymerase chain reaction (PCR).
However, some scientists used thermal bonding procedures which don’t provide good bonds even when the temperature is slightly too low. Moreover, thermal bonding also significantly alters the geometry of the channels when the temperature is high enough to ensure bonding [13].
PCB micro-features are fabricated by hot embossing with subsequent annealing of two layers using thermal bonding. Microfluidic chips made of polycarbonate can perform sample lysis, enzymatic amplification, nucleic acid isolation, amplicon labeling, and detection of pathogens [4].
Poly-methyl methacrylate (PMMA) is a cheap polymer and less hydrophobic than other plastic materials. PMMA is a commonly used material in microfluidic systems, especially for disposable chips because of its low price, rigid mechanical properties, excellent optical transparency, and compatibility with electrophoresis. This polymer also features other properties such as its ease of fabrication and modification [17].
Prepolymers consisting of the monomer MMA and the polymer PMMA were used for the replication of microfluidic chips with high resolution from different structures like PDMS or stainless steel [17].
Several methods are used for sealing PMMA-PMMA substrates, such as solvent bonding, thermal bonding, adhesive, and chemical bonding [18]. Solvent bonding generally possesses a robust and straightforward bonding process, using a solvent with a moderate dissolution rate, such as 90% ethanol, and UV light [18].
PMMA has been used as substrates for a great number of microfluidic devices including mixing analysis chips, DNA sequencers, and electrophoresis chips.
The fabrication and usage of all-Teflon chips with excellent solvent resistance is a good alternative to glass or silicon. Teflons are extremely inert to chemicals and solvents, which opened a new door to perform organic synthesis in microfluidic reactors. Teflons also present nonsticky and antifouling properties, are optically transparent, and permeable to gases. In addition, they are soft enough to make diaphragm valves and show low nonspecific protein adsorption compared with PDMS and PS [19].
Perfluorinated compounds’ surface is not only oleophobic but also hydrophobic. Perfluoroalkoxy (Teflon PFA) and polytetrafluoroethylene (PTFE) are used to build microfluidic devices and structures [4]. These materials are thermo-processable and are proposed for applications in cell cultures, high-precision assays, super-clean tools, and valve and pump fabrications.
PTFE is employed in synthesis devices, as it can tolerate a wide range of chemicals and temperatures up to 240 °C, being also naturally resistant to fouling channel blockage when aqueous solutions are involved due to its hydrophobic nature [20].
PFA is a slightly opaque perfluorinated compound, that still allows the use of fluorescence and cellular imaging. Being used for the fabrication of cheap, solvent-resistant, and reusable microfluidic chips (without contamination risk), PFA requires high-temperature embossing (∼260 °C) to mold devices. It’s an appealing material due to its melt-processability by conventional thermoplastic processing methods, adequate mechanical strength, and resistance to corrosion.
Some microfluidic devices are fabricated with polyfluoropolyether (PFPEs). Photocurable PFPEs have the potential to greatly extend the use of microfluidic devices to a wide variety of chemical applications, reducing the production time from several hours to a matter of minutes. Unlike PDMS, PFPE channels show no evidence of swelling and are compatible with all solvents involved in DNA synthesis reactions [20].
Polyurethane (PU) elastomers are characterized by their transparency, flexibility, high mechanical strength, good abrasion resistance, and capacity to withstand high pressures when compared to PDMS. PUs show properties useful for microfluidic applications while remaining cost-efficient and optimal for rapid prototyping [21].
PUs have been widely used in various applications such as artificial hearts, intra-aortic balloons, pacemaker leads, heart valves, or hemodialysis membranes. This class of materials presents hydrophobic surfaces that are essentially water-repellent. The utility of PUs can be improved by making the surface more hydrophilic and limiting non-specific protein adsorption.
Solvent casting is the most suitable technique for PU-based microfabrication, providing rapid prototyping.
Paper is a flexible, cellulose-based material that has recently become a promising microfluidic substrate for several reasons: this biocompatible material is a cheap substrate that can readily be chemically modified through composition/formulation changes or surface chemistry. However, paper can only be used for a limited type of application due to its weak mechanical properties and limited technologies.
This technology can open up the field of diagnostics and make it accessible to lower-income and limited-resource populations. Detection of analytes in paper microfluidics can be either colorimetric, electrochemical, chemiluminescence, or electrochemiluminescence [22].
Methods available for the patterning process are numerous and they define the width and length of paper microfluidic channels, with each method having its own set of advantages and limitations. For instance, inkjet and solid wax printing enable easy pattern definition and functionalization. The paper’s porous structure also allows for a combination of flow, filtering, and separation.
Microfluidics has been increasingly involved in biological research and bio-mimicking. Hydrogels, resembling the extracellular matrix, have been widely used to serve as cell support for various applications, unlike PDMS devices which are more commonly used to study tissue-level cell culture. Microchannels can be built-in hydrogels to deliver solutions, cells, and other substances.
Hydrogels are 3D networks of hydrophilic polymer chains that are situated in an aqueous medium, mainly composed of water. They are highly porous with controllable pore sizes, allowing small molecules or even bioparticles to diffuse through [23].
The diffusion of nutrition and oxygen through the gel is not adequate to support thick layer cell culture; the cells may behave differently along the gradient. The introduction of microfluidic channels into the gel matrix can realize rapid mass transfer through the bulk.
Due to low density and low strength at the macromolecule scale, hydrogels support only lower resolution (micrometer scale) in microfabrication than other polymers (nanometer scale). In addition, hydrogels with cells encapsulated may not be compatible with some microfabrication processes.
Natural or synthetic polymers form gels when crosslinked through covalent or noncovalent links. In contrast, bonding is challenging requiring melting a thin layer of the bonding surface by heat or chemicals.
Amorphous material, cyclic olefin polymers (COP) are a class of polymers based on cyclic olefin monomers and ethene, usually referred to as cyclic olefin copolymers (COC). They are synthesized by chain copolymerization of cyclic monomers with ethene, or by ring-opening polymerization of various cyclic monomers followed by hydrogenation.
COC presents interesting properties compared to commonly employed thermoplastics such as PC and PMMA. COC is relatively easy to fabricate (good moldability) and is a low-cost material. Moreover, it has innovative properties including excellent optical transmission, biocompatibility, and high chemical resistance.
However, COC also presents several potential disadvantages, such as brittleness and low heat diffusivity, which may limit its use in some applications. This material can also be attacked by non-polar organic solvents, such as toluene and hexane. Besides, COC microfluidic devices necessitate surface modification since the material presents strong hydrophobic interactions. To reduce protein adsorption, the COC chip surface can be coated using UV-initiated grafting of polyacrylamide [24].
The limitations of different single-substrate microfluidic systems drove the development of hybrid microfluidic devices to have the additional features of individual materials while avoiding their limitations. Miniaturized paper/polymer hybrid microfluidic microplates (PMMA, PDMS, etc) are cost-effective. They enable rapid immobilization of biomolecules and offer high performance in flow control, a feature that purely paper-based devices can’t operate [26].
For instance, in some PDMS/paper hybrid microfluidic systems, paper facilitates the integration of graphene oxide-based nanosensors on the chip, without any complicated surface treatment.
To that extent, rapid antibody/antigen immobilization and efficient washing are performed by using porous paper in flow-through micro-wells. Micro-channels can transfer reagents to multiple micro-wells, a method more convenient and accurate than repeated manual pipetting or costly robots. Moreover, the results of colorimetric ELISA can be observed directly within an hour without the help of measuring instruments like fluorescence microscopy.
Since its introduction, microfluidics has kept advancing along with technology, and applications are also expanding to many other disciplines. Biological and medical applications are a major focus of current research along with other areas. While glass and silicon are important materials for fabricating microfluidic chips, polymers have become the material of choice in this field, and each polymer presents some advantages and limitations. Though, PDMS is still the most commonly used material, new materials and composites with interesting features are being developed. They are more adapted to mass production with lower prices and greater adaptability.
Microfluidics is multidisciplinary and requires continued coordination between different fields, engineering physical and biological sciences, to keep improving the technology.
For more reviews about microfluidics, you can have a look here: «Microfluidics reviews».
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