Hydrogel-based logic circuits for planar microfluidics and lab-on-a-chip automation

The transport of vital nutrient supply in fluids as well as the exchange of specific chemical signals from cell to cell has been optimized over billion years of natural evolution. This model from nature is a driving factor in the field of microfluidics, which investigates the manipulation of the smallest amounts of fluid with the aim of applying these effects in fluidic microsystems for technical solutions. Currently, microfluidic systems are receiving attention, especially in diagnostics, \textit{e.g.} as SARS-CoV-2 antigen tests, or in the field of high-throughput analysis, \textit{e.g.} for cancer research. Either simple-to-use or large-scale integrated microfluidic systems that perform biological and chemical laboratory investigations on a so called Lab-on-a-Chip (LoC) provide fast analysis, high functionality, outstanding reproducibility at low cost per sample, and small demand of reagents due to system miniaturization. Despite the great progress of different LoC technology platforms in the last 30 years, there is still a lack of standardized microfluidic components, as well as a high-performance, fully integrated on-chip automation. Quite promising for the microfluidic system design is the similarity of the Kirchhoff's laws from electronics to predict pressure and flow rate in microchannel structures. One specific LoC platform technology approach controls fluids by active polymers which respond to specific physical and chemical signals in the fluid. Analogue to (micro-)electronics, these active polymer materials can be realized by various photolithographic and micro patterning methods to generate functional elements at high scalability. The so called chemofluidic circuits have a high-functional potential and provide “real” on-chip automation, but are complex in system design. In this work, an advanced circuit concept for the planar microfluidic chip architecture, originating from the early era of the semiconductor-based resistor-transistor-logic (RTL) will be presented. Beginning with the state of the art of microfluidic technologies, materials, and methods of this work will be further described. Then the preferred fabrication technology is evaluated and various microfluidic components are discussed in function and design. The most important component to be characterized is the hydrogel-based chemical volume phase transition transistor (CVPT) which is the key to approach microfluidic logic gate operations. This circuit concept (CVPT-RTL) is robust and simple in design, feasible with common materials and manufacturing techniques. Finally, application scenarios for the CVPT-RTL concept are presented and further development recommendations are proposed.:1 The transistor: invention of the 20th century 2 Introduction to fluidic microsystems and the theoretical basics 2.1 Fluidic systems at the microscale 2.2 Overview of microfluidic chip fabrication 2.2.1 Common substrate materials for fluidic microsystems 2.2.2 Structuring polymer substrates for microfluidics 2.2.3 Polymer chip bonding technologies 2.3 Fundamentals and microfluidic transport processes 2.3.1 Fluid dynamics in miniaturized systems 2.3.2 Hagen-Poiseuille law: the fluidic resistance 2.3.3 Electronic and microfluidic circuit model analogy 2.3.4 Limits of the electro-fluidic analogy 2.4 Active components for microfluidic control 2.4.1 Fluid transport by integrated micropumps 2.4.2 Controlling fluids by on-chip microvalves 2.4.3 Hydrogel-based microvalve archetypes 2.5 LoC technologies: lost in translation? 2.6 Microfluidic platforms providing logic operations 2.6.1 Hybrids: MEMS-based logic concepts 2.6.2 Intrinsic logic operators for microfluidic circuits 2.7 Research objective: microfluidic hydrogel-based logic circuits 3 Stimuli-responsive polymers for microfluidics 3.1 Introduction to hydrogels 3.1.1 Application variety of hydrogels 3.1.2 Hydrogel microstructuring methods 3.2 Theory: stimuli-responsive hydrogels 3.3 PNIPAAm: a multi-responsive hydrogel 4 Design, production and characterization methods of hydrogel-based microfluidic systems 4.1 The semi-automated computer aided design approach for microfluidic systems 4.2 The applied design process 4.3 Fabrication of microfluidic chips 4.3.1 Photoresist master fabrication 4.3.2 Soft lithography for PDMS chip production 4.3.3 Assembling PDMS chips by plasma bonding 4.4 Integration of functional hydrogels in microfluidic chips 4.4.1 Preparation of a monomer solution for hydrogel synthesis 4.4.2 Integration methods 4.5 Effects on hydrogel photopolymerization and the role of integration method 4.5.1 Photopolymerization from monomer solutions: managing the diffusion of free radicals 4.5.2 Hydrogel adhesion and UV light intensity distribution in the polymerization chamber 4.5.3 Hydrogel shrinkage behavior of different adhesion types 4.6 Comparison of the integration methods 4.7 Characterization setups for hydrogel actuators and microfluidic measurements . 71 4.7.1 Optical characterization method to describe swelling behavior 4.7.2 Setup of a microfluidic test stand 4.8 Conclusion: design, production and characterization methods 5 VLSI technology for hydrogel-based microfluidics 5.1 Overview of photolithography methods 5.2 Standard UV photolithography system for microfluidic structures 5.3 Self-made UV lithography system suitable for the mVLSI 5.3.1 Lithography setup for the DFR and SU-8 master exposure 5.3.2 Comparison of mask-based UV induced crosslinking for DFR and SU-8 5.4 Mask-based UV photopolymerization for mVLSI hydrogel patterning 5.4.1 Lithography setup for the photopolymerization of hydrogels 5.4.2 Hydrogel photopolymerization: experiments and results 5.4.3 Troubleshooting: photopolymerization of hydrogels 5.5 Conclusion: mVLSI technologies for hydrogel-based LoCs 6 Components for chemofluidic circuit design 6.1 Passive components in microfluidics 6.1.1 Microfluidic resistor 6.1.2 Planar-passive microfluidic signal mixer 6.1.3 Phase separation: laminar flow signal splitter 6.1.4 Hydrogel-based microfluidic one-directional valves 6.2 Hydrogel-based active components 6.2.1 Reversible hydrogel-based valves 6.2.2 Hydrogel-based variable resistors 6.2.3 CVPT: the microfluidic transistor 6.3 Conclusion: components for chemofluidic circuits 7 Hydrogel-based logic circuits in planar microfluidics 7.1 Development of a planar CVPT logic concept 7.1.1 Challenges of planar microfluidics 7.1.2 Preparatory work and conceptional basis 7.2 The microfluidic CVPT-RTL concept 7.3 The CVPT-RTL NAND gate 7.3.1 Circuit optimization stabilizing the NAND operating mode 7.3.2 Role of laminar flow for the CVPT-RTL concept 7.3.3 Hydrogel-based components for improved switching reliability 7.4 One design fits all: the NOR, AND and OR gate 7.5 Control measures for cascaded systems 7.6 Application scenarios for the CVPT-RTL concept 7.6.1 Use case: automated cell growth system 7.6.2 Use case: chemofluidic converter 7.7 Conclusion: Hydrogel-based logic circuits 8 Summary and outlook 8.1 Scientific achievements 8.2 Summarized recommendations from this work Supplementary information SI.1 Swelling degree of BIS-pNIPAAm gels SI.2 Simulated ray tracing of UV lithography setup by WinLens® SI.3 Determination of the resolution using the intercept theorem SI.4 Microfluidic master mold test structures SI.4.1 Polymer and glass mask comparison SI.4.2 Resolution Siemens star in DFR SI.4.3 Resolution Siemens star in SU-8 SI.4.4 Integration test array 300 μm for DFR and SU-8 SI.4.5 Integration test array 100 μm for SU-8 SI.4.6 Microfluidic structure for different technology parameters SI.5 Microfluidic test setups SI.6 Supplementary information: microfluidic components SI.6.1 Compensation methods for flow stabilization in microfluidic chips SI.6.2 Planar-passive microfluidic signal mixer SI.6.3 Laminar flow signal splitter SI.6.4 Variable fluidic resistors: flow rate characteristics SI.6.5 CVPT flow rate characteristics for high Rout Standard operation proceduresDer Transport von lebenswichtigen Nährstoffen in Flüssigkeiten sowie der Austausch spezifischer chemischer Signale von Zelle zu Zelle wurde in Milliarden Jahren natürlicher Evolution optimiert. Dieses Vorbild aus der Natur ist ein treibender Faktor im Fachgebiet der Mikrofluidik, welches die Manipulation kleinster Flüssigkeitsmengen erforscht um diese Effekte in fluidischen Mikrosystemen für technische Lösungen zu nutzen. Derzeit finden mikrofluidische Systeme vor allem in der Diagnostik, z.B. wie SARS-CoV-2-Antigentests, oder im Bereich der Hochdurchsatzanalyse, z.B. in der Krebsforschung, besondere Beachtung. Entweder einfach zu bedienende oder hochintegrierte mikrofluidische Systeme, die biologische und chemische Laboruntersuchungen auf einem sogenannten Lab-on-a-Chip (LoC) durchführen, bieten schnelle Analysen, hohe Funktionalität, hervorragende Reproduzierbarkeit bei niedrigen Kosten pro Probe und einen geringen Bedarf an Reagenzien durch die Miniaturisierung des Systems. Trotz des großen Fortschritts verschiedener LoC-Technologieplattformen in den letzten 30 Jahren mangelt es noch an standardisierten mikrofluidischen Komponenten sowie an einer leistungsstarken, vollintegrierten On-Chip-Automatisierung. Vielversprechend für das Design mikrofluidischer Systeme ist die Ähnlichkeit der Kirchhoff'schen Gesetze aus der Elektronik zur Vorhersage von Druck und Flussrate in Mikrokanalstrukturen. Ein spezifischer Ansatz der LoC-Plattformtechnologie steuert Flüssigkeiten durch aktive Polymere, die auf spezifische physikalische und chemische Signale in der Flüssigkeit reagieren. Analog zur (Mikro-)Elektronik können diese aktiven Polymermaterialien durch verschiedene fotolithografische und mikrostrukturelle Methoden realisiert werden, um funktionelle Elemente mit hoher Skalierbarkeit zu erzeugen.\\ Die sogenannten chemofluidischen Schaltungen haben ein hohes funktionales Potenzial und ermöglichen eine 'wirkliche' on-chip Automatisierung, sind jedoch komplex im Systemdesign. In dieser Arbeit wird ein fortgeschrittenes Schaltungskonzept für eine planare mikrofluidische Chiparchitektur vorgestellt, das aus der frühen Ära der halbleiterbasierten Resistor-Transistor-Logik (RTL) hervorgeht. Beginnend mit dem Stand der Technik der mikrofluidischen Technologien, werden Materialien und Methoden dieser Arbeit näher beschrieben. Daraufhin wird die bevorzugte Herstellungstechnologie bewertet und verschiedene mikrofluidische Komponenten werden in Funktion und Design diskutiert. Die wichtigste Komponente, die es zu charakterisieren gilt, ist der auf Hydrogel basierende chemische Volumen-Phasenübergangstransistor (CVPT), der den Schlüssel zur Realisierung mikrofluidische Logikgatteroperationen darstellt. Dieses Schaltungskonzept (CVPT-RTL) ist robust und einfach im Design und kann mit gängigen Materialien und Fertigungstechniken realisiert werden. Zuletzt werden Anwendungsszenarien für das CVPT-RTL-Konzept vorgestellt und Empfehlungen für die fortlaufende Entwicklung angestellt.:1 The transistor: invention of the 20th century 2 Introduction to fluidic microsystems and the theoretical basics 2.1 Fluidic systems at the microscale 2.2 Overview of microfluidic chip fabrication 2.2.1 Common substrate materials for fluidic microsystems 2.2.2 Structuring polymer substrates for microfluidics 2.2.3 Polymer chip bonding technologies 2.3 Fundamentals and microfluidic transport processes 2.3.1 Fluid dynamics in miniaturized systems 2.3.2 Hagen-Poiseuille law: the fluidic resistance 2.3.3 Electronic and microfluidic circuit model analogy 2.3.4 Limits of the electro-fluidic analogy 2.4 Active components for microfluidic control 2.4.1 Fluid transport by integrated micropumps 2.4.2 Controlling fluids by on-chip microvalves 2.4.3 Hydrogel-based microvalve archetypes 2.5 LoC technologies: lost in translation? 2.6 Microfluidic platforms providing logic operations 2.6.1 Hybrids: MEMS-based logic concepts 2.6.2 Intrinsic logic operators for microfluidic circuits 2.7 Research objective: microfluidic hydrogel-based logic circuits 3 Stimuli-responsive polymers for microfluidics 3.1 Introduction to hydrogels 3.1.1 Application variety of hydrogels 3.1.2 Hydrogel microstructuring methods 3.2 Theory: stimuli-responsive hydrogels 3.3 PNIPAAm: a multi-responsive hydrogel 4 Design, production and characterization methods of hydrogel-based microfluidic systems 4.1 The semi-automated computer aided design approach for microfluidic systems 4.2 The applied design process 4.3 Fabrication of microfluidic chips 4.3.1 Photoresist master fabrication 4.3.2 Soft lithography for PDMS chip production 4.3.3 Assembling PDMS chips by plasma bonding 4.4 Integration of functional hydrogels in microfluidic chips 4.4.1 Preparation of a monomer solution for hydrogel synthesis 4.4.2 Integration methods 4.5 Effects on hydrogel photopolymerization and the role of integration method 4.5.1 Photopolymerization from monomer solutions: managing the diffusion of free radicals 4.5.2 Hydrogel adhesion and UV light intensity distribution in the polymerization chamber 4.5.3 Hydrogel shrinkage behavior of different adhesion types 4.6 Comparison of the integration methods 4.7 Characterization setups for hydrogel actuators and microfluidic measurements . 71 4.7.1 Optical characterization method to describe swelling behavior 4.7.2 Setup of a microfluidic test stand 4.8 Conclusion: design, production and characterization methods 5 VLSI technology for hydrogel-based microfluidics 5.1 Overview of photolithography methods 5.2 Standard UV photolithography system for microfluidic structures 5.3 Self-made UV lithography system suitable for the mVLSI 5.3.1 Lithography setup for the DFR and SU-8 master exposure 5.3.2 Comparison of mask-based UV induced crosslinking for DFR and SU-8 5.4 Mask-based UV photopolymerization for mVLSI hydrogel patterning 5.4.1 Lithography setup for the photopolymerization of hydrogels 5.4.2 Hydrogel photopolymerization: experiments and results 5.4.3 Troubleshooting: photopolymerization of hydrogels 5.5 Conclusion: mVLSI technologies for hydrogel-based LoCs 6 Components for chemofluidic circuit design 6.1 Passive components in microfluidics 6.1.1 Microfluidic resistor 6.1.2 Planar-passive microfluidic signal mixer 6.1.3 Phase separation: laminar flow signal splitter 6.1.4 Hydrogel-based microfluidic one-directional valves 6.2 Hydrogel-based active components 6.2.1 Reversible hydrogel-based valves 6.2.2 Hydrogel-based variable resistors 6.2.3 CVPT: the microfluidic transistor 6.3 Conclusion: components for chemofluidic circuits 7 Hydrogel-based logic circuits in planar microfluidics 7.1 Development of a planar CVPT logic concept 7.1.1 Challenges of planar microfluidics 7.1.2 Preparatory work and conceptional basis 7.2 The microfluidic CVPT-RTL concept 7.3 The CVPT-RTL NAND gate 7.3.1 Circuit optimization stabilizing the NAND operating mode 7.3.2 Role of laminar flow for the CVPT-RTL concept 7.3.3 Hydrogel-based components for improved switching reliability 7.4 One design fits all: the NOR, AND and OR gate 7.5 Control measures for cascaded systems 7.6 Application scenarios for the CVPT-RTL concept 7.6.1 Use case: automated cell growth system 7.6.2 Use case: chemofluidic converter 7.7 Conclusion: Hydrogel-based logic circuits 8 Summary and outlook 8.1 Scientific achievements 8.2 Summarized recommendations from this work Supplementary information SI.1 Swelling degree of BIS-pNIPAAm gels SI.2 Simulated ray tracing of UV lithography setup by WinLens® SI.3 Determination of the resolution using the intercept theorem SI.4 Microfluidic master mold test structures SI.4.1 Polymer and glass mask comparison SI.4.2 Resolution Siemens star in DFR SI.4.3 Resolution Siemens star in SU-8 SI.4.4 Integration test array 300 μm for DFR and SU-8 SI.4.5 Integration test array 100 μm for SU-8 SI.4.6 Microfluidic structure for different technology parameters SI.5 Microfluidic test setups SI.6 Supplementary information: microfluidic components SI.6.1 Compensation methods for flow stabilization in microfluidic chips SI.6.2 Planar-passive microfluidic signal mixer SI.6.3 Laminar flow signal splitter SI.6.4 Variable fluidic resistors: flow rate characteristics SI.6.5 CVPT flow rate characteristics for high Rout Standard operation procedure

Rounding of Negative Dry Film Resist by Diffusive Backside Exposure Creating Rounded Channels for Pneumatic Membrane Valves

Processing of dry film resist is an easy, low-cost, and fast way to fabricate microfluidic structures. Currently, common processes are limited to creating solely rectangular channels. However, it has shown that rounded channels are necessary to ensure proper closing of pneumatic membrane valves for microfluidic devices. Here, we introduce a modification to the standard lithography process, in order to create rounded channels for microfluidic structures. Therefore, a diffuser element was inserted into in the optical path between the light source and glass substrate, which is then exposed through the backside, hence altering the exposure to the dry resist spatially. Characterization of the process was carried out with different exposure times, features sizes, and substrate thickness. The process modification is almost effortless and can be integrated in any lithography process

NASA Tech Briefs, Spring 1977

Topics: NASA TU Services: Technology Utilization services that can assist you in learning about and applying NASA technology; New Product Ideas: A summary of sel~ted innovations of value to manufacturers for the development of new products; Electronic Components and Circuits; Electronic Systems; Physical Sciences; Materials; Life Sciences; Mechanics; Machinery; Fabrication Technology; Mathematics and Information Sciences