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Microfluidic Structures for Biosensors: Comparison
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Please note this is a comparison between Version 4 by Conner Chen and Version 8 by Conner Chen.

Microfluidics is an approach based on a platform consisting of miniature micromechanical structures, channels, pumps, junctions, tubes, and sensors to enable a highly controlled manipulation and detection of liquids under test. This methodology plays a vital role in numerous fields of science and has the potential to become a tool of choice for many applications.

Microfluidics facilitates operation with small and accurately controlled volumes of liquid. Additionally, this platform can be enhanced with numerous sensors to obtain information about the properties of the liquids under test. Thus, microfluidics with embedded sensors ensures reproducibility, reliability, and accuracy of sample manipulations and measurements. 

  • microfluidics
  • biosensors
  • microstructuring
  • technology

1. Microfluidics: Basics and Materials

Microfluidics is a direction where microsystems technology-based solutions are developed for the precise transport and manipulation of fluids (liquids or gases) in small volumes, as microliters [1]. This is the main advantage of the microfluidics approach as a field of science where current advances reach picolitres handled volumes [1]. Microfluidics has experienced a significant development over the last decades following the advances in material science, chemistry, micro and nanostructuring, etc. Due to the improvement of material properties, the discovery of new chemical methods of surface passivation [2], and the development of methods and devices for high-precision structuring [3], it becomes possible to operate with ever smaller volumes of liquids and to implement sensors, optical elements, and micromechanical manipulators into the channels. All this opens new horizons for accuracy, reproducibility, and speeds up the manipulation and analysis of biological liquids. This is especially important for working with biological fluids and detecting proteins in biomedical applications. Furthermore, the absence of dead volume minimizes consumption of valuable reagents. Together with small amounts of the required material under test (MUT), it reduces the costs of experiments as a result.
Another advantage of microfluidic devices is the laminar flow conditions, which is characterized by low values of the Reynolds number. It allows greater flow control, has a linear relationship between flow rate and pressure, and the flow is characterized by non-crossing streamlines. The impact of the flow type is essential for e.g., surface plasmon resonance biosensing (which is described in Section 3). Also, laminar flow reduces the amount of air bubbles in the channel and noise [1].
The geometrical configurations of microfluidic platforms can be very different (for example, channels, tanks, separators, mixers, etc. [4][5]) and depend on the application. If microfluidic devices are created only for detecting certain biological components, they usually have a simple geometric structure in the form of one or more channels with sizes from micrometers to millimeters in cross-section. Such channels are provided with an inlet and outlet for liquid, which can be introduced to the channel using a pipette, a pump, capillary forces in the presence of the hydrophilic properties of the chip material, or by creating backpressure at the outlet. Also, a channel can be equipped with different additional components due to the sensing mechanism, e.g., lenses, micromanipulators, electrodes, etc.
In some applications, the task is not only to detect, but also to manipulate the biological sample. For example, it is necessary to sort out certain components or particles to increase the concentration of the detected component. In this case, the geometry of the microfluidic system will be more complex and passive, or active separation structures can be added to the chip [4][5]. For labelled techniques, the microfluidic chip can be expanded with microfluidic mixers [6] to blend the material under test (MUT) with fluorescent components or nanoparticles.
The most important common properties, in this case, are biocompatibility and low protein adsorption. Biocompatibility is considered here at the level of inertia of the structure materials towards biofluids in physical contact. Based on the same considerations, the following property is mandatory—the absence of proteins adsorption.
For any application the microfluidic chip materials have to be chosen carefully for their applicability in detecting proteins using the methods described below, the complexity and costs of structuring, biocompatibility, and the lack of absorption of the test material. Therefore, for the optical label-free protein detection is important that chip-body will be transparent in UV, visible and infrared (IR) spectrums, especially at the wavelength range 250–350 nm and middle IR region 2.5–20 µm. Several glass types, such as quartz glass, for example, are widely used in microfluidics with optical sensing in the UV spectrum. Borosilicate glass is also transparent in UV and at the same time in deep IR range up to the 2.9 µm wavelength. Vycor® glass at the thickness of 1 mm is transparent up to 3.1 µm. Furthermore, glass has a very low protein adsorption in comparison to polymers. At the same time, polymers are transparent at the VIS spectrum, but they are inferior to glass in UV and IR transmittance characteristics [7]. The main advantage of polymer materials for microfluidics is their relatively easy structuring. Thus, the production costs are much lower compared to glass structures. Precisely because of the simplicity and cheapness of structuring, polymers are the prevailing material of microfluidic structures with dielectric and electrochemical impedance based biosensors. Along with it, often are used material combinations, e.g., polymer/glass or polymer/silicon.
There are several examples of the sensor-microfluidic chip using a combination of the aforementioned materials. To embed the sensor into the microfluidic structure, a hard substrate is typically used as a sensor carrier. The µ-structured silicone or plastic layer is bonded on top of the sensor embedded in the carrier. Hu et al., fabricated and combined a microfluidic chip with a micro-spectrometer. The authors report the preparation of the optical system by a combination of e-beam lithography and dry etching pattern transfer processes. The microfluidic Polydimethylsiloxane (PDMS) channel was structured with molding technology, aligned, and bonded on a prepared wafer using a structured optical system [8]. Horrer et al., report about the plasmonic optical biosensor integrated into a micro-fluidic cell. Also, in this work, the optical structure is made of glass and the microfluidic channel is realized in PDMS [9]. Alsabbagh et al, reported an impedance-based biosensor realized on a glass substrate bonded with a PDMS microfluidic channel [10]. Bavil et al., used the same material combination to realize a microfluidic microparticle-labeled impedance sensor array for enhancing immunoassay sensitivity [11].
As one can see, the most common polymers for microfluidic devices are polydimethylsiloxane (PDMS), polyester, polycarbonate, etc. [12][13]. The reason for this is that silicones and plastics are non-toxic, transparent, and easy to structure. The most outstanding material is the PDMS, since, in addition to the aforementioned properties, it is gas permeable, flexible, and it can be structured using soft lithography prepared molds (see Section 2.2.1 and Section 2.2.7). As opposed to that, the alternative solutions using the aforementioned mm-thick layers of plastics (polyester, polycarbonate, etc.) have to be structured by hot embossing technology, which requires a costly stamp for the desired geometry. Hot embossing is a method which is based on impressing the plastic by a prepared metal template under certain temperature and pressure conditions. It is also possible to apply UV light or ultrasound vibrations instead of heat, in combination with mechanical force in cases where it will improve the manner of material structuring.
An important challenge that has to be addressed is the enabling of the integration of the sensors into microfluidic platforms and readout electronics. There are several sensor approaches to detect proteins in situ in microfluidics by means of optical or dielectric and electrochemical impedance spectroscopy [14]. Realization of readout electronics for these sensors requires highly-integrated miniaturized circuits realized in advanced semi-conductor technologies (e.g., complementary metal-oxide semiconductor (CMOS) technology). This would contribute to enhancing the reliability of sensor reading and enable controlling the sensors externally or wirelessly. Additionally, CMOS readout electronics would provide an advantage in terms of providing new opportunities for packaging realization. This is due to the fact that miniaturization of the control and readout electronics reduces the size of the module and enables more compact and feasible packaging solutions of the entire module, including a biocompatible microfluidic chip and integrated sensor. Impedance characterization of electrodes can be done by the classical method presented in [15]. Sensors embedded into microfluidics requires de-embedding of the interconnects between the measurement equipment (e.g., vector network analyzer (VNA)) and the terminals of the sensor. Advanced de-embedding techniques can be applied in this case [16]. By means of a miniaturized module and automated readout, one can get rid of bulky equipment by a fully autonomous system operation and wireless data transfer. The possibility to transfer the readout data wirelessly would make the system portable, and it could be even placed in an incubator, which is essential for the measurement of specific proteins, due to the requirement of regulated temperature. Some examples of an autonomous implantable integrated CMOS chip are given in [17]. Examples of building blocks required for building a wireless data communication link can be found in [18][19][20].

2. Technological Approaches for Microfluidics

The development and production of microfluidic systems is based on the manufacturing processes of semiconductor and microelectromechanical systems (MEMS) technology. Various technical processes are used which can be both additive and subtractive in nature. In addition to lithography as an interconnection technology, fundamental processes such as wet and dry chemical etching, the physical deposition of metals or the galvanic reinforcement of metallic structures can also be found in the following section [21][22].

2.1. Lithography as a Link between the Other Processes

UV lithography is an essential process for the fabrication of microfluidic components. It refers to the UV light exposure of the spin-coated layer of the photoresist through the shadow-mask. Once the layer is exposed, non-crosslinked parts of the photoresist are washed out during the development and only the crosslinked structures stay on the wafer. All the technological steps of the lithography process are shown schematically in Figure 1. It offers the possibility of transferring the previously developed design, which has often been optimized through complex Computational Fluid Dynamics (CFD) simulations, to the basic substrates. As the name suggests, this describes a process for fabricating structures with the aid of UV light. The UV light can be generated by a cross-silver vapor lamp or by aUV Light Emitting Diode (LED). Conventionally, the wavelengths of the generated radiation are in the range of 365–405 nm and are used to irradiate a photosensitive material. There are two major types of photosensitive material, positive and negative coatings. With positive coatings, the area to be exposed becomes more soluble than the non-exposed area due to the UV radiation, and can be dissolved more quickly later during the development process. The opposite process exists with negative coatings. If a negative coating, e.g., photoresist SU-8, is irradiated with UV light, a chemical reaction occurs that causes the molecular chains to lengthen and thus reduces solubility. Depending on the type of coating, these occur in different configurations, but almost all coating systems contain solvents, resins, photosensitive components and agents to optimize adhesion [21][22][23].
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Figure 1. Schematic view on soft lithography process and description of the technological steps, which are wafer preparation, photoresist coating, soft bake, UV exposure through the shadow mask, post exposure bake and development.
The actual lithography process takes place in several steps, as it is shown in Figure 1. First, the substrate surface is cleaned and freed from water. This is done in multi-stage baths (standard-clean 1 (SC1), hydrogen fluoride (HF) dip, standard-clean 2 (SC2)) to remove grease and metallic impurities. Finally, the wafers are dried on a hotplate or in an oven above 140 °C. In the second step, the substrate is usually given an adhesion promoter that is optimized for the respective photoresist and applied either by spin or steam coating. In both cases, the coating is followed by a further bake-out step to optimize the adhesion of the adhesion promoter. In the third step of UV lithography, the photoresist is applied by spin coating or spray coating. In both processes the aim is to achieve a homogeneous distribution of the coating on the substrates. The homogeneity is significantly higher with spin coating and is approx. ± 1 nm, but only permits a constant coating thickness on unstructured substrates. With spray coating, the homogeneity is usually approx. ± 250 nm, but allows coating on already structured substrates. In the so-called softbake in a convection oven or on a hotplate, the residual solvent is expelled at approx. 90–120 °C and the coating is further solidified. In the fourth step, the design structure is transferred with the help of UV light. The discussed structure area is irradiated in a mask aligner and a UV-transmitting quartz-chrome mask. The highest resolution is achieved in hard contact, where the wafer and mask are pressed together, and the poorest in the proximity method. However, the direct contact between mask and photoresist can lead to contamination or wear of the mask. As a result of the proximity method, the resolving power is reduced, but the mask and also the resist layer are protected. The distance here is between 10–20 µm. After exposure, the negative coating undergoes another heating step to cross-link the polymer chain. In the fifth step, the material to be removed is dissolved out with a lye solution or solvent and developed. In the last step, the sixth, the resist is additionally solidified once again in an oven or hotplate process to optimize adhesion or, additionally, to solidify the organic resist structure [21][22].

2.2. Oxidation of Silicon

For the development of microfluidic structures in silicon, the oxidation of the base material is an indispensable technology. In horizontal or vertical furnaces, oxygen or oxygen moistened with water flows around the pre-cleaned silicon, dry and moist oxidation. There is almost atmospheric pressure in the furnace and the temperature is between 900–1200 °C, depending on the process application. The growth rate of the silicon, which grows 56% inwards and 44% outwards, is not constant and increases with increasing oxide thickness. This is due to the increasingly longer diffusion time of the oxygen atoms through the already existing oxide layer. Dry oxides with high layer quality are mainly used for high-quality transistor dielectrics. If, on the other hand, masking layers for etching processes are of interest, moist oxides with between 100–300 nm are often used [21][24].

2.3. Chemical Vapour Deposition (CVD)

In addition to the oxidation of silicon, the deposition of silicon nitride, polysilicon or silicon carbide on the basic microfluidic substrates is also of interest for many applications, sensors, and protective and passivation coatings. These coatings can be deposited in several ways, with and without plasma assistance and at subatmospheric or atmospheric pressure. Chemical vapor deposition, CVD, is used for this purpose.
CVD is another basic technology and uses the gaseous reaction starting materials SiH4/NH3, SiH2Cl2/NH3 or SiH4/CH4, which are made to react by thermal energy or plasma support. The reaction end product is usually a solid as well as a volatile component. The solid serves as a useful layer for the applications described, and can make the substrate materials such as silicon, glasses or even polymer layers more resistant or, for example, change the wetting properties [21][25].

2.4. Wet and Dry Chemical Structuring of Substrate Material

The structuring of silicon and glass is a basic technology for the production of microfluidic systems. In addition to liquid etching on an acid or alkali basis, various etching gases are also used which are specially adapted to the substrate material.
In the 1980s, the wet chemical structuring of silicon was a fundamental technology for the development of microfluidic systems. For example, even then silicon or glass was patterned and used in printheads by Hewlett Packard [26]; silicon can be directionally patterned using potassium hydroxide (KOH). The typical pyramid shape is formed, for example, by silicon (100), and enables the production of nozzles when a substrate is completely etched through. Silicon can be structured very stably and with high reproducibility [22].
In addition to the wet-chemical structuring of silicon, the development of the so-called Bosch process, today also known as deep reactive ion etching, was another milestone in the further development of plasma patterning methods. In this process, the silicon substrate surface is initially covered with a photoresist mask or silicon oxide and the desired design, and then patterned using a reactive etching gas (SF6) in a combination of physical and chemical attack. In the second etch process subsection, complete passivation of the substrate surface is performed using a plasma-generated polymer of C4F8 and argon (carrier gas). The generated polymer layer covers both the etch trench bottom and the existing etch trench wall. If the combination of physical and chemical etch attack is now performed, the etch trench bottom and the etch trench wall are etched more intensively. Thus, it is possible to etch nearly vertical structures into silicon with a defined wall roughness and given structure at width to depth ratios of 1:100 and more [21][25][27].

2.5. 3D Printing of Microfluidic Systems

The technological development and realization of microfluidic systems is not limited to the common semiconductor and MEMS processes but is also possible with a wide variety of 3D printing processes. The associated processes use, among other things, curing resists or remelting polymers. The following is a brief description of the most important processes for manufacturing microfluidic systems in 3D printing [28][29][30][31].

2.5.1 FDM or FFF Printing

The pioneer in the development of fused filament fabrication or fused deposition modeling (FFF or FDM) systems was the company Stratasys. This process was developed in 1988 by S. Scott Crump, a co-founder of Stratasys. As the name suggests, the object to be produced is made from a fused wire. The wire, usually a plastic, is melted and pressed through a nozzle. This nozzle can be a few hundred µm or even a few millimetres in diameter and is movably suspended above a heated build plate made of glass or metal. When the filament, which has been heated above its liquefaction point, hits the heated construction plate, it solidifies and allows the partially cooled polymer to be built up layer by layer. The structural accuracy of the manufactured object image depends on several parameters, including nozzle diameter, layer height, processing temperature of the filament, build temperature, build plate temperature, etc. [31].
The materials used depend directly on the intended use and the technical possibilities of the printer. Thus, it is possible to use low-melting and at the same time very inexpensive polylactic acid (PLA) for rigid and simple structures without great technical demands. Even with low-priced printers, it is possible to process PLA [32]. If the technical requirements increase due to lower water absorption and temperature resistance, acrylonitrile butadiene styrene (ABS), or polycarbonate (PC), are used. However, the processing demands increase, for example, in the pressure temperature from 200 °C to 230 °C or 270 °C for PC [33]. The processing of high-performance polymers is also possible today. For example, production of microfluidic elements in polyetheretherketone (PEEK) can be realized at 440 °C. Printed elements made of PEEK also enable the analysis of corrosive media [34][35].
One obstacle of FDM technology is the production of overhangs. In many cases, this is only possible with the help of support material. This support material temporarily stabilizes free-standing areas of the print during the printing process and sometimes considerably extends the processing time. After printing, this support material must be removed in an additional post-treatment step; this can be done mechanically (breaking, grinding) or chemically (dissolving with water or lye solution). An environmentally friendly and at the same time water-soluble support material is polyvinyl alcohol (PVA) [36]. Unfortunately, FDM 3D printing has several disadvantages such as comparably low printing quality and speed, and layer-by-layer FDM printing can lead to shrinking and warping.
As already mentioned, the minimum print resolution depends on many different parameters (design, capabilities of the printer, print material). For example, the structure size is <0.1 mm and the layer height of <0.1 mm and wall thicknesses of <0.1 mm [37].

2.5.2 Stereolithography (SLA) Printing

The stereolithography process, or SLA process for short, is another method for creating microfluidic structures. Here, however, the polymer to be used later is not thermally melted but cured with the help of light quanta. The polymer mixtures to be used (resin) have a photoactive component and can be cured with the help of a laser. The printing plate is usually immersed upside down in the polymer. The laser then writes the first support layer on the plate surface to improve adhesion between the resin and the base plates. After completion of the first adhesion layer, the solidified polymer layer is pulled out of the liquid polymer matrix by a few µm, and the next structure is cured with the laser on the already solidified surface. The step-by-step production, i.e., layer by layer, is similar to the FDM process. Here, too, self-supporting structures are only possible with the help of support structures. However, in contrast to FDM, no second water-soluble material can be used for SLA printing. After printing, excess resin residues are washed out with IPA, isopropanol, and the support structures are removed with mechanical aids [30][38].
The structure resolution of approx. 25 µm is significantly lower than that of the FDM process.

2.6. Sub-Micron Structuring

Recent developments in lasers opened up a new era for mesoscale microfluidics. Two-photon polymerization based on 3D laser lithography (3DLL) applied to micro-optics [39], microfluidics [40] and photonics [41] allow for the achievement of nano- and micro-feature enabled functionality in micro-structures. 3DLL is a flexible manufacturing method, and it is possible to print almost any kind of sub-micron 3D object with nano-resolution. As it is a laser lithography process, the structured materials are polymers. Nevertheless, a wide range of materials allows finding the optimal one for the chosen application. Using this method, it is possible to structure the 3D objects even inside of the fabricated microfluidic channel [42]. A schematic view of the 3DLL technology is shown in Figure 2.
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Figure 2. Schematics of 3D laser lithography 3DLL technology, which is based on next steps: substrate preparation, applying photoresist by pipet, soft bake on the hot plate, femto-second laser writing, and development in the liquid developer. The development step (5) reveals the final free-standing micrometer or sub-micrometer size structure.
Glass is a more appropriate material for optofluidics. Laser-structuring is applicable in this case as well, but it works differently than lithography. It “grinds” an object of the desired shape from a piece of glass or a special light-sensitive material, and does not expose it layer by layer. Such an approach was applied to fabricate micro-lenses with submicron precision. To make a lens it is necessary to apply several layers of special material to the glass disc which will prevent the evaporating of the glass or polymer, and then process it with femtosecond pulses, reapply the “protective layer” and repeat this procedure until the lens is ready.

2.7. Molding and Bonding

Molding technology is used for polymer structuring. Polydimethylsiloxane (PDMS) is one of the most well-known materials which can be structured by this method. It is highly hydrophobic, is transparent in the visible spectrum, is flexible and biocompatible. These characteristics made PDMS attractive for several biomedical applications and microfluidics [45].
Molding technology consists of the following steps: (1) Polymer preparation (liquid phase); (2) Pouring out or spin-coating liquid material on the master mold; (3) Curing; and (4) Releasing the structured layer, which replicates the master mold geometry (Figure 3). In the PDMS example, as a first step, the base and curing component have to be mixed in a ratio of 10:1. Viscous material has to be poured out on the preparation by soft lithography mold. After 48 h of curing at room temperature or 2 h at 60 °C, the structured layer can be released. Next, half of the microfluidic channel has to be bonded to any structured or non-structured layer.
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Figure 3. Schematics of the molding technology. The liquid polymer is applied on the prepared mold (2), cured (3) and released (4) with the replicated from the mold structures.
Bonding is a technological process intended to combine several layers of carrier material. Upon completion of the bonding process, these layers are merged into a single unified microfluidic structure. The surface of the two layers, which need to be bonded, is usually exposed to a plasma or chemical treatment, adhesives, and temperature treatment. It creates active groups on the material surface which form a covalent connection to another layer. One can specify these steps for bonding of the PDMS and glass. This type of polymer requires the oxygen plasma treatment, then alignment of the two layers and heating up to 80 °C for 10 min. The sensor electrodes are deposited on the glass surface and the microfluidic channel is bonded on top. The disadvantage of PDMS is protein adsorption due to its loose nature. During the analysis of the liquids with high protein concentration it does not contribute to the result value. But for the precise measurements, another transparent polymer can be chosen that is less elastic and adsorbing. For the hard polymers, structuring can be applied by the hot embossing method and adhesives to provide reliable bonding. For some of the photoresists, UV exposure and heat/pressure treatment are needed to achieve a covalent bond [47].

2.8. Surface Functionalization to Avoid Protein Adsorption

The ability of the materials to adsorb proteins in the thin layer below the surface de-pends on their structural properties. Glass exhibits properties of the crystalline structure, therefore, the protein adsorption is very low, and it is used for many biological processes and applications. Polymers have a structure of polymer chains which can be differently orientated and entangled. Also, polymer chain density and porosity can vary strongly from one polymer to another. Therefore, polymers are not the ideal material for biological applications, as they adsorb and absorb a wide variety of molecules.
The previously mentioned polydimethylsiloxane (PDMS) is a porous and hydrophobic polymer material [48]. PDMS’ porosity is a result of the flexibility of its polymer chains and the large distance between them. Thus, it has a high level of protein adsorption and absorption [49]. Due to the variety of beneficial properties mentioned above, PDMS is a commonly used material in micro-fluidics. Therefore, several interesting approaches to modify its surface were developed. Recently, Gökaltun et al., reported an interesting method to avoid protein adsorption in PDMS. The authors added an additional component during the mixing of PDMS base with a curing agent. As a result, the surface becomes hydrophilic only in the presence of liquid in the channel, and self-assembling smart copolymers comprised of poly(ethylene glycol) (PEG) block the adsorption of the particles [2]. Ren et al., created an approach to avoid salinization of the PDMS and achieve low protein adsorption and hydrophilicity. They fabricated wax-modified PDMS channels with the paraffin peristaltic valves for micellar electrokinetic chromatography. The alternative methods to prevent adsorption and absorption of the proteins are Teflon coating of the surface, water-repellent spraying, and perfluorodecyl trichlorosilane (FDTS) blending [50]. You et al., developed a modern method to avoid the absorption of fluorescent molecules into PDMS. Therefore, we created a nanoadhesive layer deposited via initiated chemical vapor deposition (iCVD) [51].

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