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PMC:7143804 / 13455-27290 JSONTXT 12 Projects

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Id Subject Object Predicate Lexical cue
T110 0-2 Sentence denotes 2.
T111 3-25 Sentence denotes Design and Fabrication
T112 27-31 Sentence denotes 2.1.
T113 32-61 Sentence denotes Microfluidic Structure Design
T114 62-174 Sentence denotes The microfluidic structure consists of two chambers, i.e., a reaction chamber and a temperature monitor chamber.
T115 175-226 Sentence denotes In Figure 2, a close-up of the final chip is shown.
T116 227-315 Sentence denotes For clarity reasons, the two microfluidic structures are colored with food coloring dye.
T117 316-764 Sentence denotes The reaction chamber is based on the work of Bruijns et al. [36] and its dimensions are chosen in such way that the internal volume of the reaction chamber is the same as the reaction volume of the used Illustra GenomiPhi V2 DNA amplification kit (GE Healthcare Life Sciences, Eindhoven, The Netherlands) together with the EvaGreen dye solution (Biotium, Fremont, CA, USA), while maintaining an as low as possible surface-area-to-volume ratio [44].
T118 765-1110 Sentence denotes Using SolidWorks 2018 computer-aided design (CAD) software (Dassault Systemes, Vélizy-Villacoublay, France), the 3D image of the chip is drawn and with the use of the AutoDesk HSMWorks computer-aided manufacturing (CAM) plug-in (Autodesk Inc., San Rafael, CA, USA), this image is transferred into a computer numerical control (CNC) milling code.
T119 1111-1199 Sentence denotes The total chip size is 3 cm by 3 cm and contains an inlet and outlet of 1.5 mm diameter.
T120 1200-1297 Sentence denotes The inlet and outlet are of such size that the reaction chamber can be filled using pipette tips.
T121 1298-1390 Sentence denotes In between the inlet and outlet, a rectangular reaction chamber of 10 mm by 3 mm is located.
T122 1391-1492 Sentence denotes Two trapezoid structures are placed in the tapered channels between the inlet/outlet and the chamber.
T123 1493-1537 Sentence denotes The function of these trapezoids is twofold:
T124 1538-1698 Sentence denotes First, they minimize the dead volume between the inlet/outlet and the reaction chamber, locating as much as possible of the reaction mixture inside the chamber.
T125 1699-1752 Sentence denotes Second, they provide support for the chamber closure.
T126 1753-1910 Sentence denotes A stadium-shaped channel of 1.5 mm wide and 1.0 mm deep is located next to the reaction chamber, in such way that this channel is also covered by the heater.
T127 1911-1962 Sentence denotes This channel serves as temperature monitor chamber.
T128 1963-2066 Sentence denotes A thermocouple is inserted in this channel for real-time monitoring of the temperature inside the chip.
T129 2067-2161 Sentence denotes This way, a more accurate temperature of the reaction mixture inside the chip can be obtained.
T130 2162-2232 Sentence denotes Via a feedback loop, the input potential can be changed when required.
T131 2233-2322 Sentence denotes In Figure 3, the SolidWorks design of the chamber-based chip with both chambers is shown.
T132 2323-2399 Sentence denotes In Figure A1, in Appendix A, the technical drawing of the chip can be found.
T133 2401-2405 Sentence denotes 2.2.
T134 2406-2439 Sentence denotes Resistive Heater Structure Design
T135 2440-2613 Sentence denotes A resistive heater structure will be placed at the bottom side of the chip using shadow masks and a metal deposition method capable of being used for large-scale production.
T136 2614-2717 Sentence denotes A meandering heater design is chosen, as this minimizes the input power required to heat up the heater.
T137 2718-3071 Sentence denotes This is evident from Equation (1), which is the relation between Joule’s law, Ohm’s law, and Pouillet’s law. (1) P=Across−section∗V2ρres,i∗lheater Here, P is the input power, Across−section is the cross-sectional area of the resistor, V is the input potential, ρres,i is the resistivity of resistor material i, and lheater is the length of the resistor.
T138 3072-3270 Sentence denotes This makes a meandering structure, or any other narrow line structure, a quite often used pattern for heaters or electrodes within micro-electromechanical structures and microfluidics [26,29,54,55].
T139 3271-3505 Sentence denotes MDA is being done at temperatures of around 30 °C [50], which is lower than, for example, temperatures required for HDA (64 °C) [9] or LAMP (65 °C) [11] and the required PCR temperatures of Chung et al. (95 °C, 54 °C, and 72 °C) [28].
T140 3506-3583 Sentence denotes However, most amplification methods require a DNA denaturation step at 95 °C.
T141 3584-4273 Sentence denotes Equation (2) is used to make an estimation of the required heating powers for a COC–H2O–COC stack (in the real device, the upper plate is an adhesive PCR foil, but the thermal properties of this foil are unknown). (2) P=ΔTRth=ΔT∗Aheated∗κCOClCOC,1+κH2OlH2O+κCOClCOC,2+h Here, Rth is defined as the sum of all thermal resistances in series: (3) Rth=1h×Aheated+∑isubstancesliκi×Aheated Here, P is the required power, ΔT is the temperature difference, Rth is the thermal resistance, Aheated is the heated area, h is the convective heat transfer coefficient (being 10 W m−2 K−1 for convection to air [56]), κi is the thermal conductivity of substance i, and li is the thickness of substance i.
T142 4274-4315 Sentence denotes Values for κi can be found in Appendix B.
T143 4316-4396 Sentence denotes From Equation (3), the product Rth×A can be defined as the sum of 1/h and li/κi.
T144 4397-4619 Sentence denotes Based on this summation, one can conclude that the convective heat transfer to the air is the most present heat transfer mechanism within the system (begin almost a factor 100 higher than the heat lost in the COC and H2O).
T145 4620-4812 Sentence denotes This is also evident from solving Equation (2) for every individual temperature differences within the system and also including convective heat transfer directly from the heater into the air.
T146 4813-5073 Sentence denotes If a heated area of 7.7 mm by 10.1 mm is assumed, which covers both the reaction chamber and the temperature monitor chamber, and a system consisting of 1 mm COC–0.5 mm H2O–0.1 mm COC is assumed, than the heater temperatures and powers in Table 1 are required.
T147 5074-5187 Sentence denotes These are all in the workable range when a COC of a proper grade is chosen (e.g., TOPAS 6017 has a Tg of 170 °C).
T148 5188-5308 Sentence denotes The only side note here is that at higher temperatures, the temperature gradient through the system also becomes larger.
T149 5309-5386 Sentence denotes This can be eliminated by using double-sided heating, like Chung et al. [28].
T150 5387-5637 Sentence denotes To determine the optimal heater width and heater spacing in the heated area, a parametric study using COMSOL Multiphysics 5.3a finite element method simulations with the Heat Transfer in Solids (ht) package is done (COMSOL Inc., Burlington, MA, USA).
T151 5638-5798 Sentence denotes The model is designed such that it consists of two parallel rectangles of COC (in the real device, the upper plate is an adhesive PCR foil) with H2O in between.
T152 5799-5883 Sentence denotes The meandering heater are assumed to be lines at the bottom side of the layer stack.
T153 5884-6022 Sentence denotes This reduces the required complexity of the mesh tremendously, as the heater in the real device will be approximately 100 nm in thickness.
T154 6023-6091 Sentence denotes The heater temperature is set at a constant temperature of 303.15 K.
T155 6092-6214 Sentence denotes This makes the heater material independent and the model purely focused on the heat transfer inside the COC–H2O–COC stack.
T156 6215-6269 Sentence denotes All used values and equations are given in Appendix B.
T157 6270-6393 Sentence denotes The layer stack is meshed with an extremely fine mapped mesh consisting of 280.650 elements with average quality of 0.9966.
T158 6394-6558 Sentence denotes A parametric sweep from 0.3 mm to 2.0 mm, in steps of 0.1 mm, is done for both the heater width (wheater) and the heater spacing (sheater), giving 324 combinations.
T159 6559-6742 Sentence denotes The simulations are solved by using the fully coupled, direct Pardiso solver on a custom-build and 40% CPU overclocked simulation computer, containing the equipment listed in Table 2.
T160 6743-6938 Sentence denotes To validate whether the metal tracks can withstand the required current, a quick analysis is done for the four extreme cases (i.e., wheater of 0.3 mm and 2.0 mm and sheater of 0.3 mm and 2.0 mm).
T161 6939-7058 Sentence denotes In the same heated area of 7.7 mm by 10.1 mm a 100 nm (theater) thick heater track consisting of rectangles is assumed.
T162 7059-7164 Sentence denotes The total amount of large and smaller interconnecting rectangles for all 4 cases is estimated in Table 3.
T163 7165-7559 Sentence denotes Based on the polynomial approximation equations for the resistivity of Au and Pt (ρres,i, where i is either Au or Pt) which COMSOL MultiPhysics 5.3a uses (Equations (4) and (5)) and Equation (6) an estimation is made for the required input currents and the created current densities (defined as Ii/Across−section, in A m−2) when the heater is operated at 129.4 mW to get a temperature of 95 °C.
T164 7560-7849 Sentence denotes These estimations are also given in Table 3. (4) ρres,Au(T)=−2.210068×10−9+9.057611×10−11∗Tfor60≤T<400−4.632985×10−14∗T2+6.950205×−17∗T3 (5) ρres,Pt(T)=−1.927892×10−8+5.233699×10−10∗Tfor160≤T<600−4.107885×10−13∗T2+6.694129×−16∗T3−4.447775×10−19∗T4 (6) Ii=PRi=P∗Across−sectionρres,i∗lheater
T165 7850-8167 Sentence denotes In which ρres,i is the resistivity, T is the temperature, Ii is the current going through the resistor, Pi is the input power, R is the resistance of the resistor, lheater is the length of the resistor, and Across−section is the cross-sectional area of the resistor defined as width times thickness (wheater×theater).
T166 8168-8221 Sentence denotes The subscript i denotes the material, being Au or Pt.
T167 8222-8373 Sentence denotes All these current densities are below the critical current densities for Au and Pt, which are around 1010 A m−2 [57] and 1011 A m−2 [58], respectively.
T168 8374-8500 Sentence denotes Therefore, any possible combination of heater width and heater spacing will give a resistive that can withstand its operation.
T169 8502-8506 Sentence denotes 2.3.
T170 8507-8518 Sentence denotes Fabrication
T171 8519-8691 Sentence denotes COC [42] is chosen as polymeric substrate because of its biocompatibility, optical transparency, physical resistance, chemical resistance, electrical insulation, and price.
T172 8692-8843 Sentence denotes This copolymer consists of two monomers, an apolar bridged cyclic hydrocarbon (norbornene) monomer and a linear, lesser apolar, linear ethene monomers.
T173 8844-9039 Sentence denotes Injection molded COC plates (10 cm by 10 cm and 1.5 mm thickness) of the grade TOPAS 6017 (see Figure 4a) are obtained via Kunststoff-Zentrum Leipzig (Kunststoff-Zentrum gGmbH, Leipzig, Germany).
T174 9040-9142 Sentence denotes This grade is chosen because of its high norbornene content, giving it a relatively high Tg of 170 °C.
T175 9143-9315 Sentence denotes This minimizes the chance of melting during the milling process and decreases the chance of heater failure due to a deforming substrate during operation of the heater [28].
T176 9316-9485 Sentence denotes The microfluidic structure explained in Section 2.1 is CNC-milled using a Mikron WF 21C milling machine (Mikron SA Agno, Agno, Switzerland), as can be seen in Figure 4b.
T177 9486-9574 Sentence denotes Milling is a very fast prototyping technique and chosen because of its flexibility [41].
T178 9575-9665 Sentence denotes The milling creates a surface roughness, which increases the surface-area-to-volume ratio.
T179 9666-9808 Sentence denotes This roughness increases the chance of inhibition during the amplification due to the interaction of the used chemicals with the surface [44].
T180 9809-9960 Sentence denotes It also causes a considerable loss of optical transparency, which could obstruct the potential use of in situ fluorescence detection in future devices.
T181 9961-10045 Sentence denotes Therefore, a chemical post-treatment with cyclohexane vapor is done (see Figure 4c).
T182 10046-10276 Sentence denotes Such treatment dissolves a thin outer layer of the COC substrate and causes reflowing of the surface roughness due to the surface tension of the material, restoring the optical transparency and reducing the surface roughness [59].
T183 10277-10375 Sentence denotes CNC milling and subsequent cyclohexane vapor post-treatment are less suitable for mass production.
T184 10376-10440 Sentence denotes However, COC has the possibility of being injection molded [42].
T185 10441-10488 Sentence denotes The used substrates are made using this method.
T186 10489-10729 Sentence denotes This is a large-scale production method and could lower the costs of the eventual product and it eliminates the cyclohexane vapor post-treatment, as injection-molded chips would have the same optical transparency as the pristine substrates.
T187 10730-10854 Sentence denotes Guckenberger et al. mention production costs of $ 47 per simple microfluidic device when only 50 pieces are fabricated [41].
T188 10855-10932 Sentence denotes This price is expected to drop drastically when large numbers are fabricated.
T189 10933-11092 Sentence denotes A metal is deposited on the backside of the substrate using two laser-cut metal (Mo) shadow masks to outline the shape of the resistive heater (see Figure 4d).
T190 11093-11224 Sentence denotes Mo has a smaller coefficient of thermal expansion than stainless steel, and therefore gives less deformation during the deposition.
T191 11225-11327 Sentence denotes Metals of interest are Au or Pt, which are commonly used metals to function as resistive heaters [54].
T192 11328-11655 Sentence denotes The deposition methods studied are DC magnetron sputtering using a custom-build machine (Techno Centrum voor Onderwijs en Onderzoek, University of Twente, Enschede, The Netherlands) and e-beam physical vapor deposition (evaporation) using a Balzers BAK 600 CE (Oerlikon Balzers limited, Balzers, Principality of Liechtenstein).
T193 11656-11794 Sentence denotes Both deposition methods are capable of large-scale production, which will lower the production costs in the large-volume production stage.
T194 11795-12239 Sentence denotes The metal and deposition method will be chosen based on the metal adhesion performances on the COC substrate, which is studied using the Scotch tape test [60,61], and the resistance versus temperature behavior in the range 20 °C to 100 °C, which is measured in a Heraeus T5025 oven (Heraeus Holding GmbH, Hanau, Germany), customized with electrical readout and connected to a custom-build National Instruments LabVIEW program (Austin, TX, USA).
T195 12241-12245 Sentence denotes 2.4.
T196 12246-12255 Sentence denotes Operation
T197 12256-12408 Sentence denotes The chambers with the resistive heater on the backside, are intensively cleaned by rinsing with acetone, MilliQ DI water, ethanol, and isopropanol [45].
T198 12409-12487 Sentence denotes Each cleaning step was done 3 times and the chips are blow dried using N2 gas.
T199 12488-12711 Sentence denotes After drying, the chambers are closed using Microseal “B” PCR plate sealing foil from Bio-Rad (Bio-Rad Inc., Hercules, CA, USA), which is cut in the proper size and manually attached on top of the substrate (see Figure 4e).
T200 12712-12961 Sentence denotes The DNA, reactants and buffer solutions from the Illustra GenomiPhi V2 DNA amplification kit and an EvaGreen fluorescence dye are pipetted inside the chip using the inlet aperture, after which the inlet and outlet are closed using the same PCR foil.
T201 12962-13143 Sentence denotes An input potential is applied on the resistive heater using a Keithley 2602 SYSTEM SourceMeter (Cleveland, OH, USA) until they acquire the desired temperature for the amplification.
T202 13144-13318 Sentence denotes The temperature is real-time monitored by inserting a 162 series RS Technics thermocouple K (RS Components B.V., Haarlem, The Netherlands) in the temperature monitor chamber.
T203 13319-13415 Sentence denotes The thermocouple is read out with a Tenma 72-7715 Thermometer (Premier Farnell Ltd., Leeds, UK).
T204 13416-13519 Sentence denotes The source and the read-out of the thermocouple are operated using a custom-programmed LabVIEW program.
T205 13520-13668 Sentence denotes The initial potential is based on the heater characterization measurements, but will be adjusted according to the feedback-loop of the thermocouple.
T206 13669-13835 Sentence denotes Detection of the amplification is done ex-situ by using quartz cuvets and an Horiba Scientific FluoroMax+ spectrofluorometer (Horiba Scientific, Piscataway, NJ, USA).