Complex Microfluidic Networks Research Articles

Coumarin-Based Photodegradable Hydrogels Enable Two-Photon Subtractive Biofabrication at 300 mm s-1.

Spatiotemporally controlled two-photon photodegradation of hydrogels has gained increasing attention for high-precision subtractive tissue engineering. However, conventional photolabile hydrogels often have poor efficiency upon two-photon excitation in the near-infrared (NIR) region and thus require high laser dosage that may compromise cell activity. As a result, high-speed two-photon hydrogel erosion in the presence of cells remains challenging. Here we introduce the design and synthesis of efficient coumarin-based photodegradable hydrogels to overcome these limitations. A set of photolabile coumarin-functionalized polyethylene glycol linkers are synthesized through a Passerini multicomponent reaction. After mixing these linkers with thiolated hyaluronic acid, semi-synthetic photodegradable hydrogels are formed in situ via Michael addition crosslinking. The efficiency of photodegradation in these hydrogels is significantly higher than that in nitrobenzyl counterparts upon two-photon irradiation at 780 nm. A complex microfluidic network mimicking the bone microarchitecture is successfully fabricated in preformed coumarin hydrogels at high speeds of up to 300 mm s-1 and low laser dosage down to 10 mW. Further, we demonstrate fast two-photon printing of hollow microchannels inside a hydrogel to spatiotemporally direct cell migration in 3D. Collectively, these hydrogels may open new avenues for fast laser-guided tissue fabrication at high spatial resolution.

Femtosecond laser rapid prototyping and characterization of microfluidic device for particles sorting

Rapid prototyping methods for the fabrication of polymeric labs-on-a-chip (LoC) are on the rise, as they allow high degrees of precision and flexibility. In this contest, the flexibility of ultrafast laser technology enables the rapid prototyping and high-precision micromachining of 3D LoC devices with complex microfluidic channel networks. In this paper, we describe the realization process of a microfluidic tool for fully inertial particles sorting. The microfluidic network was realized in polymethyl methacrylate (PMMA), exploiting femtosecond laser technology. The multilayer device was assembled through a facile and low-cost solvent-assisted method. In particular, we studied the particle focusing in curved inertial microfluidic channel with trapezoidal cross section. A particles focusing along the walls of the device, sensitive to particle size and flow rate, was observed based on the principle of Dean-coupled inertial migration in spiral microchannel.

Pressure-driven generation of complex microfluidic droplet networks

Pressure-driven generation of complex microfluidic droplet networks

Predicting the fluid behavior of random microfluidic mixers using convolutional neural networks.

With the various applications of microfluidics, numerical simulation is highly recommended to verify its performance and reveal potential defects before fabrication. Among all the simulation parameters and simulation tools, the velocity field and concentration profile are the key parts and are generally simulated using finite element analysis (FEA). In our previous work [Wang et al., Lab Chip, 2016, 21, 4212-4219], automated design of microfluidic mixers by pre-generating a random library with the FEA was proposed. However, the duration of the simulation process is time-consuming, while the matching consistency between limited pre-generated designs and user desire is not stable. To address these issues, we inventively transformed the fluid mechanics problem into an image recognition problem and presented a convolutional neural network (CNN)-based technique to predict the fluid behavior of random microfluidic mixers. The pre-generated 10 513 candidate designs in the random library were used in the training process of the CNN, and then 30 757 brand new microfluidic mixer designs were randomly generated, whose performance was predicted by the CNN. Experimental results showed that the CNN method could complete all the predictions in just 10 seconds, which was around 51 600× faster than the previous FEA method. The CNN library was extended to contain 41 270 candidate designs, which has filled up those empty spaces in the fluid velocity versus solute concentration map of the random library, and able to provide more choices and possibilities for user desire. Besides, the quantitative analysis has confirmed the increased compatibility of the CNN library with user desire. In summary, our CNN method not only presents a much faster way of generating a more complete library with candidate mixer designs but also provides a solution for predicting fluid behavior using a machine learning technique.

Microchannels with Self-Pumping Walls.

When asymmetric Janus micromotors are immobilized on a surface, they act as chemically powered micropumps, turning chemical energy from the fluid into a bulk flow. However, such pumps have previously produced only localized recirculating flows, which cannot be used to pump fluid in one direction. Here, we demonstrate that an array of three-dimensional, photochemically active Au/TiO2 Janus pillars can pump water. Upon UV illumination, a water-splitting reaction rapidly creates a directional bulk flow above the active surface. By lining a 2D microchannel with such active surfaces, various flow profiles are created within the channels. Analytical and numerical models of a channel with active surfaces predict flow profiles that agree very well with the experimental results. The light-driven active surfaces provide a way to wirelessly pump fluids at small scales and could be used for real-time, localized flow control in complex microfluidic networks.

A Stimuli-Responsive Hydrogel Array Fabrication Scheme for Large-Scale and Wearable Microfluidic Valving

Programmable microfluidic valving enables controlled routing and compartmentalized manipulation of fluid within networks of microfluidic channels-capabilities which can be harnessed to implement an automated, massively parallelized, and diverse set of bioanalytical operations in large-scale microfluidics (lab-on-a-chip) and wearable (labon-the-body) applications. Stimuli-responsive hydrogels are suitable base materials to construct programmable microfluidic valving interfaces: once embedded in a microfluidic channel, their volumetric shrinkage/expansion (in response to stimulus) can be exploited to open/close microfluidic channels. However, to adapt them for the envisioned applications, critical fabrication challenges including robustness (e.g., complete channel sealing), scalability (forming arrays of valves with high yield and throughput), miniaturization of the valve actuation interface, and mechanical compatibility (flexibility for wearability) must be addressed. Here, we devise a simple and low-cost fabrication scheme to create arrays of stimuli-responsive hydrogels (e.g., thermo-responsive) and optional stimulus embodiments (e.g., microheaters) with compact footprints and within complex microfluidic networks. Within the framework of this fabrication scheme, we specifically: 1) introduced an ex situ hydrogel hydroconditioning step to achieve full channel sealing; 2) optimized the valve performance to achieve maximal volumetric response; and 3) utilized mechanically flexible and thin device layers to ensure compatibility for wearable applications. We illustrated the scalability of the fabricated valves and their enabling microfluid management capabilities, by demonstrating fluid routing/compartmentalization within valve-gated square matrix and radial tree matrix microfluidic networks.

Modeling of capillary-driven microfluidic networks using electric circuit analogy

Capillary-driven flow in complex microfluidic devices is increasingly encountered in life science applications, and powerful modeling tools are necessary to assist the design of these devices. In this work, we present a modeling framework for capillary-driven flow in closed complex microfluidic networks using electric circuit analogy. The model handles two immiscible fluid phases, including the capillary pressure jump across the interface(s) between the phases, in a large variety of fluidic structures. As outputs, the position and velocity of each interface in the analyzed microfluidic network are provided as a function of time. Single channels, successive channels of different dimensions, tapered channels, micropillar arrays, flow splitters, mixing of two liquids, and the presence of vents can be modeled and combined in different complex structures. Static and dynamic contact angles can be employed. Advancing and receding interfaces can both be modeled. The model was validated against both experimental and analytical results for specific microfluidic structures. Furthermore, the capabilities of the model are demonstrated using a complex microfluidic network.

Characterization of Dielectrophoresis Based Relay-Assisted Molecular Communication Using Analogue Transmission Line

Increase in research focus on developing lab-on-chip based devices like Body-on-chip and Organ-on-chip, have led to a higher number of functional entities in lab-on-chip. This, in turn, has led to increasingly complex microfluidic channel networks. Thus, there arises a need to characterize the microfluidic networks and establish communication among various entities of lab-on-chip. Electric circuit analogy is one of the options for the characterization of such a microfluidic network. Further, the dielectrophoresis relay-assisted molecular communication system can help in establishing interconnection among various entities using molecular communication. We propose to use an electrical transmission line technique to model and characterize the dielectrophoresis relay-assisted molecular communication system. We use transmission line parameters- resistance, inductance, and capacitance for characterizing the said molecular communication system. The numerical results obtained show that the peak concentration reduces as a function of distance, and the attenuation of the transmitted signal decreases with the increase in the number of relays in the system. This implies that the dielectrophoresis relay-assisted molecular communication system can help in transmitting low-frequency concentration signal with low attenuation. The results obtained are consistent with those obtained with already existing techniques. Thus, the transmission line technique can be utilized for characterizing a microfluidic system for molecular communication.

MOFBOTS: Metal-Organic-Framework-Based Biomedical Microrobots.

Motile metal-organic frameworks (MOFs) are potential candidates to serve as small-scale robotic platforms for applications in environmental remediation, targeted drug delivery, or nanosurgery. Here, magnetic helical microstructures coated with a kind of zinc-based MOF, zeolitic imidazole framework-8 (ZIF-8), with biocompatibility characteristics and pH-responsive features, are successfully fabricated. Moreover, it is shown that this highly integrated multifunctional device can swim along predesigned tracks under the control of weak rotational magnetic fields. The proposed systems can achieve single-cell targeting in a cell culture media and a controlled delivery of cargo payloads inside a complex microfluidic channel network. This new approach toward the fabrication of integrated multifunctional systems will open new avenues in soft microrobotics beyond current applications.

Vascularized microfluidic platforms to mimic the tumor microenvironment.

Microfluidic technology has led to the development of advanced in vitro tumor platforms that overcome the challenges of in vivo animal and in vitro two dimensional models. This paper presents platform designs and methods used to develop complex vascularized in vitro models to mimic the tumor microenvironment. Features of these platforms include a continuous, aligned endothelium that allows for cell-cell interactions between vasculature and tumor cells. A novel platform for fabrication of a single endothelialized microchannel encased within a collagen platform hosting breast cancer cells was developed and utilized to study the influence of cellular interaction on transport phenomenon through vasculature in a hyperpermeable tumor microenvironment. This platform relies on subtractive tissue engineering fabrication techniques. Through confocal imaging we have demonstrated that the platform produces enhanced vessel leakiness recapitulating physiological features of the tumor microenvironment. The influence of tumor endothelial interactions on transport of particles was also demonstrated. Additionally, we designed two more complex and intricate endothelialized microfluidic networks by combining lithographic techniques with additive tissue engineering methods. We created a network platform consisting of interconnected microchannels to model a highly vascularized system and successfully perfused the system with fluorescent particles. Finally, we developed a physiologically representative in vitro microfluidic platform with vasculature patterned from in vivo data showing the versatility of these systems to replicate the complex geometries of tumor microvasculature and dynamically measured particle transport. Overall, we have shown the ability to develop functional microfluidic vascular tumor platforms of varying complexities and demonstrated their utility for studying spatial particle transport within these systems.

Microfluidics: Accelerated Biofluid Filling in Complex Microfluidic Networks by Vacuum‐Pressure Accelerated Movement (V‐PAM) (Small 33/2016)

Microfluidics: Accelerated Biofluid Filling in Complex Microfluidic Networks by Vacuum‐Pressure Accelerated Movement (V‐PAM) (Small 33/2016)

Accelerated Biofluid Filling in Complex Microfluidic Networks by Vacuum-Pressure Accelerated Movement (V-PAM).

Rapid fluid transport and exchange are critical operations involved in many microfluidic applications. However, conventional mechanisms used for driving fluid transport in microfluidics, such as micropumping and high pressure, can be inaccurate and difficult for implementation for integrated microfluidics containing control components and closed compartments. Here, a technology has been developed termed Vacuum-Pressure Accelerated Movement (V-PAM) capable of significantly enhancing biofluid transport in complex microfluidic environments containing dead-end channels and closed chambers. Operation of the V-PAM entails a pressurized fluid loading into microfluidic channels where gas confined inside can rapidly be dissipated through permeation through a thin, gas-permeable membrane sandwiched between microfluidic channels and a network of vacuum channels. Effects of different structural and operational parameters of the V-PAM for promoting fluid filling in microfluidic environments have been studied systematically. This work further demonstrates the applicability of V-PAM for rapid filling of temperature-sensitive hydrogels and unprocessed whole blood into complex irregular microfluidic networks such as microfluidic leaf venation patterns and blood circulatory systems. Together, the V-PAM technology provides a promising generic microfluidic tool for advanced fluid control and transport in integrated microfluidics for different microfluidic diagnosis, organs-on-chips, and biomimetic studies.

Additively Manufactured Microfluidics-Based “Peel-and-Replace” RF Sensors for Wearable Applications

This paper demonstrates the first-of-its-kind additively manufactured microfluidics-based flexible RF sensor, combining microfluidics, inkjet-printing technology, and soft lithography, which could potentially enable the first “real-world” wearable “smart skin” applications. A low-cost, rapid, low-temperature, and zero-waste fabrication process is introduced, which can be used to realize complex microfluidic channel networks with virtually any type of sensing element embedded. For proof-of-concept purposes, a reusable and flexible microfluidics sensor was prototyped using this process, which only requires 0.6- $\mu {\text {L}}$ fluid volume to produce a 44% frequency shift between an empty ( $\epsilon _{r}=1$ ) and a water-filled channel ( $\epsilon _{r}=73$ ), demonstrating a sensitivity that is higher than most previously reported microfluidics-based microwave sensors. Seven different fluids were used to measure the sensitivity of the prototype and an overall sensitivity of $24\%/ \log (\epsilon _{r})$ was observed. The “peel-and-replace” capability of the presented sensor not only facilitates the cleaning process for sensor reusability, but it also enables sensitivity tunability. For bent/conformed configurations, the sensor’s functionality is good even for a bending radius down to 7 mm, demonstrating its great flexibility. After bending multiple times, the sensor still exhibits a very good performance repeatability, which verifies its reusability feature. The introduced additively manufactured RF microfluidics-based sensor would be well suited for numerous wearable and conformal fluid sensing applications (e.g., bodily fluids analyzing and food monitoring), while it could also be utilized in a variety of microfluidics-reconfigurable microwave components.

Lab-on-a-chip-Systementwicklung für den Laboralltag

Miniaturization of biological and chemical assays in lab-on-a-chip systems is a highly topical field of research. Full custom centric design of dropletbased microfluidic lab-on-a-chip systems leads to a high system integration level and design complexity. We report on a software toolkit for modelling droplet traffic and processing for complex microfluidic networks. As a result, the advantages of lab-on-a-chip systems will be accessible for more people through the easy, versatile and efficient transformation of complicated laboratory workflows to easy to use lab-on-a-chip applications.

Flow patterning in Hele-Shaw configurations using non-uniform electro-osmotic slip

We present an analytical study of electro-osmotic flow in a Hele-Shaw configuration with non-uniform zeta potential distribution. Applying the lubrication approximation and assuming thin electric double layer, we obtain a pair of uncoupled Poisson equations for the pressure and depth-averaged stream function, and show that the inhomogeneous parts in these equations are governed by gradients in zeta potential parallel and perpendicular to the applied electric field, respectively. We obtain a solution for the case of a disk-shaped region with uniform zeta potential and show that the flow field created is an exact dipole, even in the immediate vicinity of the disk. In addition, we study the inverse problem where the desired flow field is known and solve for the zeta potential distribution required in order to establish it. Finally, we demonstrate that such inverse problem solutions can be used to create directional flows confined within narrow regions, without physical walls. Such solutions are equivalent to flow within channels and we show that these can be assembled to create complex microfluidic networks, composed of intersecting channels and turns, which are basic building blocks in microfluidic devices.

Automated Microfluidic Platform for Serial Polymerase Chain Reaction and High-Resolution Melting Analysis.

We report the development of an automated genetic analyzer for human sample testing based on microfluidic rapid polymerase chain reaction (PCR) with high-resolution melting analysis (HRMA). The integrated DNA microfluidic cartridge was used on a platform designed with a robotic pipettor system that works by sequentially picking up different test solutions from a 384-well plate, mixing them in the tips, and delivering mixed fluids to the DNA cartridge. A novel image feedback flow control system based on a Canon 5D Mark II digital camera was developed for controlling fluid movement through a complex microfluidic branching network without the use of valves. The same camera was used for measuring the high-resolution melt curve of DNA amplicons that were generated in the microfluidic chip. Owing to fast heating and cooling as well as sensitive temperature measurement in the microfluidic channels, the time frame for PCR and HRMA was dramatically reduced from hours to minutes. Preliminary testing results demonstrated that rapid serial PCR and HRMA are possible while still achieving high data quality that is suitable for human sample testing.

Steering liquid metal flow in microchannels using low voltages.

Liquid metals based on gallium, such as eutectic gallium indium (EGaIn) and Galinstan, have been integrated as static components in microfluidic systems for a wide range of applications including soft electrodes, pumps, and stretchable electronics. However, there is also a possibility to continuously pump liquid metal into microchannels to create shape reconfigurable metallic structures. Enabling this concept necessitates a simple method to control dynamically the path the metal takes through branched microchannels with multiple outlets. This paper demonstrates a novel method for controlling the directional flow of EGaIn liquid metal in complex microfluidic networks by simply applying a low voltage to the metal. According to the polarity of the voltage applied between the inlet and an outlet, two distinct mechanisms can occur. The voltage can lower the interfacial tension of the metal via electrocapillarity to facilitate the flow of the metal towards outlets containing counter electrodes. Alternatively, the voltage can drive surface oxidation of the metal to form a mechanical impediment that redirects the movement of the metal towards alternative pathways. Thus, the method can be employed like a 'valve' to direct the pathway chosen by the metal without mechanical moving parts. The paper elucidates the operating mechanisms of this valving system and demonstrates proof-of-concept control over the flow of liquid metal towards single or multiple directions simultaneously. This method provides a simple route to direct the flow of liquid metal for applications in microfluidics, optics, electronics, and microelectromechanical systems.

Correspondence Between Electronics and Fluids in MEMS: Designing Microfluidic Systems Using Electronics

It is well known that the classical laws of circuits have equivalents in fluid movement if certain conditions are met. Usually, equivalence with linear circuits requires laminar flow, which is a typical condition in a microelectromechanical system (MEMS). However, fluidic devices, which are nonlinear in nature, can also have an electronic counterpart, and the tools and procedures used in electronic design can be applied to microfluidic systems. A complete description of the electronic-fluidic correspondence, focused especially on MEMS, can increase the number of ways to design microfluidic networks and open new ways of operating them. The modeling of complex microfluidic networks, in particular, applications, demonstrate the usefulness of the analogy.

Toward microfluidic design automation: a new system simulation toolkit for the in silico evaluation of droplet-based lab-on-a-chip systems

Miniaturization of biological and chemical assays in lab-on-a-chip systems is a highly topical field of research. The pressure-driven droplet-based microfluidic platform is a promising way to realize these miniaturized systems by expanding the capability of assays with special features that are unreached by traditional workflows. Full custom centric design of droplet-based microfluidic lab-on-a-chip systems leads to a high system integration level and design complexity. In our work, we report on a software toolkit based on the Kirchhoff laws for modeling droplet traffic and processing for even complex microfluidic networks. Experimental validation of the simulation results was performed utilizing directional droplet transport switching in a circular channel element. This structure can be employed as a benchmark system for the experimental validation of the obtained simulation results. As a result of these experiments, our design and simulation toolkit meet the requirements for a versatile and low-risk development of custom lab-on-a-chip devices. Together with our conceptual model of microfluidic networks, most of the development problems arising with complex lab-on-a-chip applications can be solved. Due to the high computational speed, the algorithm allows an interactive in silico evaluation of even complex sample-processing workflows in droplet-based microfluidic devices prior any preparation of prototypes. Summarizing the developed toolkit may become the foundation for the future development of software tools for a microfluidic design automation. As a result of this new way of simulation-based application-driven development, the advantages of lab-on-a-chip will be accessible for more people through the easy, versatile and efficient transformation from complex laboratory workflows to compact and easy to use lab-on-a-chip applications.

Reconfigurable microfluidic hanging drop network for multi-tissue interaction and analysis.

Integration of multiple three-dimensional microtissues into microfluidic networks enables new insights in how different organs or tissues of an organism interact. Here, we present a platform that extends the hanging-drop technology, used for multi-cellular spheroid formation, to multifunctional complex microfluidic networks. Engineered as completely open, 'hanging' microfluidic system at the bottom of a substrate, the platform features high flexibility in microtissue arrangements and interconnections, while fabrication is simple and operation robust. Multiple spheroids of different cell types are formed in parallel on the same platform; the different tissues are then connected in physiological order for multi-tissue experiments through reconfiguration of the fluidic network. Liquid flow is precisely controlled through the hanging drops, which enable nutrient supply, substance dosage and inter-organ metabolic communication. The possibility to perform parallelized microtissue formation on the same chip that is subsequently used for complex multi-tissue experiments renders the developed platform a promising technology for 'body-on-a-chip'-related research.