Cell Culture Chip Research Articles

Non-invasive measurement of wall shear stress in microfluidic chip for osteoblast cell culture using improved depth estimation of defocus particle tracking method.

The development of a non-invasive method for measuring the internal fluid behavior and dynamics of microchannels in microfluidics poses critical challenges to biological research, such as understanding the impact of wall shear stress (WSS) in the growth of a bone-forming osteoblast. This study used the General Defocus Particle Tracking (GDPT) technique to develop a non-invasive method for quantifying the fluid velocity profile and calculated the WSS within a microfluidic chip. The GDPT estimates particle motion in a three-dimensional space by analyzing two-dimensional images and video captured using a single camera. However, without a lens to introduce aberration, GDPT is prone to error in estimating the displacement direction for out-of-focus particles, and without knowing the exact refractive indices, the scaling from estimated values to physical units is inaccurate. The proposed approach addresses both challenges by using theoretical knowledge on laminar flow and integrating results obtained from multiple analyses. The proposed approach was validated using computational fluid dynamics (CFD) simulations and experimental video of a microfluidic chip that can generate different WSS levels under steady-state flow conditions. By comparing the CFD and GDPT velocity profiles, it was found that the Mean Pearson Correlation Coefficient is 0.77 (max = 0.90) and the Mean Intraclass Correlation Coefficient is 0.66 (max = 0.82). The densitometry analysis of osteoblast cells cultured on the designed microfluidic chip for four days revealed that the cell proliferation rate correlates positively with the measured WSS values. The proposed analysis can be applied to quantify the laminar flow in microfluidic chip experiments without specialized equipment.

A simulated microgravity-oriented AIE probe-ECM hydrogel-integrated chip for cell culture and superoxide anion radical detection

Human space activities have been continuously increasing. Astronauts experiencing spaceflight are faced with health problems caused by special space environments such as microgravity, and the investigation of cell injury is fundamental. The development of a platform capable of cell culture and injury detection is the prerequisite for the investigation. Constructing a platform suitable for special conditions in space life science research is the key issue. The ground-based investigation is an indispensable part of the research. Accordingly, a simulated microgravity (SMG)-oriented integrated chip platform capable of 3D cell culture and in situ visual detection of superoxide anion radical (O2•−) is developed. SMG can cause oxidative stress in human cells, and O2•− is one of the signaling molecules. Thus, a O2•−-responsive aggregation-induced emission (AIE) probe is designed, which shows high selectivity and sensitivity to O2•−. Moreover, the probe exhibits abilities of long-term and wash-free staining to cells due to the AIE behavior, which is precious for space cell imaging. Meanwhile, a chip with a high-aspect-ratio chamber for adequate medium storage for the lack of the perfusion system during the SMG experiment and a cell culture chamber which can integrate the extracellular matrix (ECM) hydrogel for the bioinspired 3D cell culture is fabricated. In addition, a porous membrane is introduced between the chambers to prevent the hydrogel from separating during the SMG experiment. The afforded AIE probe-ECM hydrogel-integrated chip can achieve 3D culturing of U87-MG cells and in situ fluorescent detection of endogenous O2•− in the cells after long-term staining under SMG. The chip provides a powerful and potential platform for ground-based investigation in space life science and biomedical research.

A Comprehensive Review of Organ-on-a-Chip Technology and Its Applications.

Organ-on-a-chip (OOC) is an emerging technology that simulates an artificial organ within a microfluidic cell culture chip. Current cell biology research focuses on in vitro cell cultures due to various limitations of in vivo testing. Unfortunately, in-vitro cell culturing fails to provide an accurate microenvironment, and in vivo cell culturing is expensive and has historically been a source of ethical controversy. OOC aims to overcome these shortcomings and provide the best of both in vivo and in vitro cell culture research. The critical component of the OOC design is utilizing microfluidics to ensure a stable concentration gradient, dynamic mechanical stress modeling, and accurate reconstruction of a cellular microenvironment. OOC also has the advantage of complete observation and control of the system, which is impossible to recreate in in-vivo research. Multiple throughputs, channels, membranes, and chambers are constructed in a polydimethylsiloxane (PDMS) array to simulate various organs on a chip. Various experiments can be performed utilizing OOC technology, including drug delivery research and toxicology. Current technological expansions involve multiple organ microenvironments on a single chip, allowing for studying inter-tissue interactions. Other developments in the OOC technology include finding a more suitable material as a replacement for PDMS and minimizing artefactual error and non-translatable differences.

PTOLEMI: Personalized Cancer Treatment through Machine Learning-Enabled Image Analysis of Microfluidic Assays.

Contemporary personalized cancer diagnostic approaches encounter multiple challenges. The presence of cellular and molecular heterogeneity in patient samples introduces complexities to analysis protocols. Conventional analyses are manual, reliant on expert personnel, time-intensive, and financially burdensome. The copious data amassed for subsequent analysis strains the system, obstructing real-time diagnostics at the "point of care" and impeding prompt intervention. This study introduces PTOLEMI: Python-based Tensor Oncological Locator Examining Microfluidic Instruments. PTOLEMI stands out as a specialized system designed for high-throughput image analysis, particularly in the realm of microfluidic assays. Utilizing a blend of machine learning algorithms, PTOLEMI can process large datasets rapidly and with high accuracy, making it feasible for point-of-care diagnostics. Furthermore, its advanced analytics capabilities facilitate a more granular understanding of cellular dynamics, thereby allowing for more targeted and effective treatment options. Leveraging cutting-edge AI algorithms, PTOLEMI rapidly and accurately discriminates between cell viability and distinct cell types within biopsy samples. The diagnostic process becomes automated, swift, precise, and resource-efficient, rendering it well-suited for point-of-care requisites. By employing PTOLEMI alongside a microfluidic cell culture chip, physicians can attain personalized diagnostic and therapeutic insights. This paper elucidates the evolution of PTOLEMI and showcases its prowess in analyzing cancer patient samples within a microfluidic apparatus. While the integration of machine learning tools into biomedical domains is undoubtedly in progress, this study's innovation lies in the fusion of PTOLEMI with a microfluidic platform-an integrated, rapid, and independent framework for personalized drug screening-based clinical decision-making.

미세유체장치 내 박테리아 세포 배양을 위한 저비용 항온·항습 배양기 개발

Advances in cell culture technology have improved the understanding of the physiological principles of cells. Recently, the development of microfluidic chips has made it possible to observe single cells in a massively parallelized and accurate manner. However, in order to maximize the availability of the microfluidic cell chip, it is essential to use an incubator that can isolate the cell culture chip from the outside while minimizing contamination and maintaining the temperature and humidity required for cell culture for a long time period. Here, we developed a thermo-hygrostat incubator consisting of an Arduino-based feedback control module for controlling a temperature and humidity complex sensor, a humidifier, and a heater. The temperature and humidity of the incubator could be actively changed according to the needs and application by simple editing control variables of Arduino coding. To demonstrate the efficiency of the device, we conducted an experiment comparing the growth of bacterial cells and obtained optimal conditions necessary for culture. In conclusion, it is expected that the newly developed thermo-hygrostat incubator can be used for a variety of purposes that require active control of temperature and humidity, as well as for long-term cultivation of bacterial cells inside a microfluidic chip.

Construction of a three-dimensional urothelium on-chip with barrier function based on urinary flow microenvironment

The urothelium covers the inner surface of the urinary tract, forming a urinary tract barrier. Impairment of the integrity and dysfunction of the urinary tract barrier is associated with the occurrence and development of various diseases. The development of a three-dimensional model of the urothelium is critical for pathophysiological studies of this site, especially under physiological fluid shear stress stimulated by the urinary flow. In this study, a urothelium on-chip is fabricated with micromilling and replica molding techniques, which contains a microfluidic chip for cell culture and a pump-based fluid perfusion system. The mechanical properties of the human urinary tract are simulated by adjusting the concentration and degree of amino substitution of the gelatin methacrylate hydrogel. The matrix stiffness is similar to the natural urinary tract. Pulsatile flow and periodic flow are provided to simulate the fluid environment of the upper and lower urinary tracts, respectively. The results show that the physiological fluid shear stress could promote the differentiation and maturation of urothelial cells. The model could simulate the three-dimensional structure of urothelium and urinary flow microenvironment, showing morphological structure close to the natural urothelium, specific differentiation and maturation markers (uroplakin 2, cytokeratin 20), and urothelial barrier function.

Design and simulation of a novel integrated microfluidic chip for cell isolation and culture.

The lab on a chip is utilized as a background and a substrate for creating a proper flow for cellular processes in medicine. In this study, the concepts of cell isolation and cell transfer methods have been discussed. After that, the device of separation and transfer systems has been designed, simulated, and verified by placing the frequency of particle separation and droplet formation, which is tried to introduce a new device that can be used in cellular studies. The optimal operation conditions for the problem have also been investigated. High separation efficiency (99%) could be achieved when the velocity of the sample inlet in the microchannel separator is 180μm/s. Also, a microfluidic device for droplet generation has been designed to transfer the isolated cells to the culture medium. For this purpose, the frequency of droplet production must be synchronized with particle ejection frequency and equals 9.09Hz.

Rapid Customization and Manipulation Mechanism of Micro-Droplet Chip for 3D Cell Culture.

A full PDMS micro-droplet chip for 3D cell culture was prepared by using SLA light-curing 3D printing technology. This technology can quickly customize various chips required for experiments, saving time and capital costs for experiments. Moreover, an injection molding method was used to prepare the full PDMS chip, and the convex mold was prepared by light-curing 3D printing technology. Compared with the traditional preparation process of micro-droplet chips, the use of 3D printing technology to prepare micro-droplet chips can save manufacturing and time costs. The different ratios of PDMS substrate and cover sheet and the material for making the convex mold can improve the bonding strength and power of the micro-droplet chip. Use the prepared micro-droplet chip to carry out micro-droplet forming and manipulation experiments. Aimed to the performance of the full PDMS micro-droplet chip in biological culture was verified by using a solution such as chondrocyte suspension, and the control of the micro-droplet was achieved by controlling the flow rate of the dispersed phase and continuous phase. Experimental verification shows that the designed chip can meet the requirements of experiments, and it can be observed that the micro-droplets of sodium alginate and the calcium chloride solution are cross-linked into microspheres with three-dimensional (3D) structures. These microspheres are fixed on a biological scaffold made of calcium silicate and polyvinyl alcohol. Subsequently, the state of the cells after different time cultures was observed, and it was observed that the chondrocytes grew well in the microsphere droplets. The proposed method has fine control over the microenvironment and accurate droplet size manipulation provided by fluid flow compared to existing studies.

A Cell Culture Chip with Transparent, Micropillar-Decorated Bottom for Live Cell Imaging and Screening of Breast Cancer Cells.

In the recent years, microfabrication technologies have been widely used in cell biology, tissue engineering, and regenerative medicine studies. Today, the implementation of microfabricated devices in cancer research is frequent and advantageous because it enables the study of cancer cells in controlled microenvironments provided by the microchips. Breast cancer is one of the most common cancers in women, and the way breast cancer cells interact with their physical microenvironment is still under investigation. In this study, we developed a transparent cell culture chip (Ch-Pattern) with a micropillar-decorated bottom that makes live imaging and monitoring of the metabolic, proliferative, apoptotic, and morphological behavior of breast cancer cells possible. The reason for the use of micropatterned surfaces is because cancer cells deform and lose their shape and acto-myosin integrity on micropatterned substrates, and this allows the quantification of the changes in morphology and through that identification of the cancerous cells. In the last decade, cancer cells were studied on micropatterned substrates of varying sizes and with a variety of biomaterials. These studies were conducted using conventional cell culture plates carrying patterned films. In the present study, cell culture protocols were conducted in the clear-bottom micropatterned chip. This approach adds significantly to the current knowledge and applications by enabling low-volume and high-throughput processing of the cell behavior, especially the cell–micropattern interactions. In this study, two different breast cancer cell lines, MDA-MB-231 and MCF-7, were used. MDA-MB-231 cells are invasive and metastatic, while MCF-7 cells are not metastatic. The nuclei of these two cell types deformed to distinctly different levels on the micropatterns, had different metabolic and proliferation rates, and their cell cycles were affected. The Ch-Pattern chips developed in this study proved to have significant advantages when used in the biological analysis of live cells and highly beneficial in the study of screening breast cancer cell–substrate interactions in vitro.

An integrated microfluidic chip for alginate microsphere generation and 3D cell culture.

Three-dimensional (3D) hydrogel microspheres have attracted increasing attention as cell culture carriers. The system of hydrogel microspheres provides great advantages for cell growth owing to its high surface-to-volume ratio and biocompatible environment. However, an integrated system that includes microsphere generation, microsphere capture and in situ culture together has not been realized yet. Here we present a multifunctional microfluidic device to accomplish the overall process including cell-laden microsphere generation, online demulsification and dynamic-culture. The microfluidic device can produce massive monodispersed alginate microspheres and allows us to immobilize the alginate microspheres and record bacterial growth. Moreover, the microspheres provide a suitable environment through the mechanical properties of soft tissues, leading to high cell viability, proliferation, activity and biocompatibility. We believe that this versatile and biocompatible platform will provide a more reliable analysis tool for tissue engineering and cell therapy.

In silico design and fabrication of an SFI chip-based microspheroid culture system.

The emergence of microfluidic devices and computational fluid dynamics (CFD) has propelled the need for next-generation biomimetic cell culture platforms that are flexible for monitoring and regulation. Therefore, this study evaluated a CFD application in an in silico-designed and spheroid-based flow integration 3D cell culture chip (SFI chip) to illustrate cell culture, drug screening, cytokine delivery, and differentiation of cells in a platform that partially recapitulates the natural environment. Our results show that a flow rate of 0.05 mL h-1 or less induced no physical stress in the SFI chip (15 mm), and uniform cell spheroids (approximately 200 μm) were formed across the platform. The cultured cells were tested in several experimental contexts (co-culture, drug screening, cytokine delivery, and differentiation), demonstrating the usefulness of computational simulation in expediting discovery and simple and effective means to scale the production of standardized cell spheroids cultured under dynamic and natural conditions. Advanced cell culture technologies can be used to accelerate research and discovery and the preclinical and clinical development of cell and cell-free therapies for urgent medical needs.

Adhesive-Based Fabrication Technique for Culture of Lung Airway Epithelial Cells with Applications in Cell Patterning and Microfluidics.

This work describes a versatile and cost-effective cell culture method for micropatterning and growing adherent cells on porous membranes using pressure-sensitive double-sided adhesives. This technique also allows cell culture using conventional methods and their easy integration into microfluidic chip devices. Adhesives can be used to form different patterns of cultured cells, which can be used for cell proliferation and wound-healing models. To demonstrate the viability of our system, we evaluate the toxicity effect of five different adhesives on two distinct airway epithelial cell lines and show functional applications for cell patterning and microfluidic cell culture chip fabrication. We developed a sandwiched microfluidic device that enabled us to culture cells in a submerged condition and transformed it into a dynamic platform when required. The viability of cells and their inflammatory responses to IL-1β stimulation were investigated. Our technique is applicable for conventional culturing of cells, widely available in biomedical research labs, while enabling the introduction of perfusion for an advanced dynamic cell culture model when needed.

Organ-on-a-chip: Determine feasibility of a human liver microphysiological model to assess long-term steroid metabolites in sports drug testing.

A fundamental challenge in preventive doping research is the study of metabolic pathways of substances banned in sport. However, the pharmacological predictions obtained by conventional in vitro or in vivo animal studies are occasionally of limited transferability to humans according to an inability of in vitro models to mimic higher order system physiology or due to various species-specific differences using animal models. A more recently established technology for simulating human physiology is the "organ-on-a-chip" principle. In a multichannel microfluidic cell culture chip, 3-dimensional tissue spheroids, which can constitute artificial and interconnected microscale organs, imitate principles of the human physiology. The objective of this study was to determine if the technology is suitable to adequately predict metabolic profiles of prohibited substances in sport. As model compounds, the frequently misused anabolic steroids, stanozolol and dehydrochloromethyltestosterone (DHCMT) were subjected to human liver spheroids in microfluidic cell culture chips. The metabolite patterns produced and circulating in the chip media were then assessed by LC-HRMS/(MS) at different time points of up to 14 days of incubation at 37°C. The overall profile of observed glucurono-conjugated stanozolol metabolites excellently matched the commonly found urinary pattern of metabolites, including 3'OH-stanozolol-glucuronide and stanozolol-N-glucuronides. Similarly, but to a lower extent, the DHCMT metabolic profile was in agreement with phase-I and phase-II biotransformation products regularly seen in postadministration urine specimens. In conclusion, this pilot study indicates that the "organ-on-a-chip" technology provides a high degree of conformity with traditional human oral administration studies, providing a promising approach for metabolic profiling in sports drug testing.

Hydrostatic pressure promotes migration and filamin-A activation in fibroblasts with increased p38 phosphorylation and TGF-β production

Fibroblast migration is closely regulated by the mechanical characteristics in surrounding microenvironment. While increased interstitial hydrostatic pressure (HP) is a hallmark in many pathological and physiological conditions, little is known about how the HP affects fibroblast motility. Using cell-culture chips with elevated HP conditions, we showed that 20 cmH2O HP significantly accelerated fibroblast migration. The HP-induced migration acceleration was dependent on the augmentation of transforming growth factor-β1, and correlated with the activation of filamin A via the phosphorylation of p38 mitogen-activated protein kinase. Our results suggest that interstitial HP elevation associated with various pathological states could significantly regulate fibroblast migration.

Protein Micropatterning in 2.5D: An Approach to Investigate Cellular Responses in Multi-Cue Environments.

The extracellular microenvironment is an important regulator of cell functions. Numerous structural cues present in the cellular microenvironment, such as ligand distribution and substrate topography, have been shown to influence cell behavior. However, the roles of these cues are often studied individually using simplified, single-cue platforms that lack the complexity of the three-dimensional, multi-cue environment cells encounter in vivo. Developing ways to bridge this gap, while still allowing mechanistic investigation into the cellular response, represents a critical step to advance the field. Here, we present a new approach to address this need by combining optics-based protein patterning and lithography-based substrate microfabrication, which enables high-throughput investigation of complex cellular environments. Using a contactless and maskless UV-projection system, we created patterns of extracellular proteins (resembling contact-guidance cues) on a two-and-a-half-dimensional (2.5D) cell culture chip containing a library of well-defined microstructures (resembling topographical cues). As a first step, we optimized experimental parameters of the patterning protocol for the patterning of protein matrixes on planar and non-planar (2.5D cell culture chip) substrates and tested the technique with adherent cells (human bone marrow stromal cells). Next, we fine-tuned protein incubation conditions for two different vascular-derived human cell types (myofibroblasts and umbilical vein endothelial cells) and quantified the orientation response of these cells on the 2.5D, physiologically relevant multi-cue environments. On concave, patterned structures (curvatures between κ = 1/2500 and κ = 1/125 μm–1), both cell types predominantly oriented in the direction of the contact-guidance pattern. In contrast, for human myofibroblasts on micropatterned convex substrates with higher curvatures (κ ≥ 1/1000 μm–1), the majority of cells aligned along the longitudinal direction of the 2.5D features, indicating that these cells followed the structural cues from the substrate curvature instead. These findings exemplify the potential of this approach for systematic investigation of cellular responses to multiple microenvironmental cues.

Additive manufacturing of a 3D vascular chip based on cytocompatible hydrogel

Development of a three-dimensional (3D) vascular microfluidic chip is one of the important challenges for the study vascular-related diseases and new drugs. To date, however, realization of in vivo-like blood vessel chips based on soft- or photo-lithographic fabrication methods have limitations such as complex fabrication processes, tedious manual labor, and frequent assembly failure. In this study, we describe the development of a 3D cell culture chip by utilizing a stereolithographic printer. The microfluidic chip was fabricated using a resin made of 30% (v/v in water) poly(ethylene glycol) diacrylate (MW = 700) (30% PEG-DA-700), a UV initiator (Irgacure-819 (IRG)) and a photosensitizer (2-isopropylthioxanthone (ITX)) for constructing a cytocompatible hydrogel structure. The 3D-printed cell culture chip is transparent, enabling cell culture and observation of cell proliferation. Endothelial cells were cultured to mimic in vivo-like blood vessel architecture within the 3D-printed chip. After EAhy926 cell cultivation, cell viability was confirmed by a live/dead cell assay and cultured cells were stained with Calcein-AM (Green) and Ethidium homodim-1 (Red). In addition, endothelial cells were successfully cultured in a 3D-printed vascular tube-like architecture in PEG-DA-700. Creating a vascular microfluidic chip with 30% PEG-DA-700 hydrogel using automated 3D-printing processes reduces fabrication steps and time, avoids any assembly and bonding, and economizes manufacturing cost. We believe our stereolithographic 3D-printing method for fabricating a 3D-printed vascular chip provides a cost-effective, convenient, simple, and reproducible route to vascular-related disease modelling and drug screening analyses.

A Three-Dimensional Microfluidic Device for Monitoring Cancer and Chemotherapy-Associated Platelet Activation.

Platelet activation and the risk of thrombosis are increased in cancer patients, especially after chemotherapy. Our previous studies indicated that chemotherapy-induced platelet activation is largely due to endothelial cell damage. Thus, simple in vitro tests, such as aggregometry, are not desirable tests to predict platelet responsiveness to different chemotherapeutic agents because other contributory factors, such as tumor cells, endothelial cells, and the flow rate of platelets, also contribute to the formation of cancer-associated thrombosis. Therefore, developing a platelet detection system, which includes all possible risk parameters, is necessary. In the present study, we described a microengineered microfluidic system that contained a drug concentration generator, cancer cell culture chip, and three-dimensional (3D) circular microvascular model covered with a confluent endothelial layer and perfused with human platelets at a stable flow rate. Doxorubicin was injected through two injection sites. Endothelial cell injury was evaluated by counting, cell cytoskeleton observation, and the level of IACM1 and ET-1 in endothelial cells or a culture medium. Prestained platelets were perfused into the artificial blood vessel, and platelet-endothelial cell adhesion was measured. We found that (i) MCF7 cell-released factors had a cytotoxicity effect on both endothelial cells and platelets. (ii) We confirmed that doxorubicin-induced platelet activation was endothelial cell-dependent. (iii) A lower dosage of doxorubicin (0–2.0 μM) induced platelet activation, while a higher dosage of doxorubicin (2.0–4.0 μM) led to platelet death. Our findings indicated that platelet-endothelial cell adhesion could be used as a diagnostic marker of platelet activation, providing a simple and rapid detective way to predict platelet responsiveness before or during chemotherapy.

Fabrication of a hydroxyapatite-PDMS microfluidic chip for bone-related cell culture and drug screening

Bone is an important part of the human body structure and plays a vital role in human health. A microfluidic chip that can simulate the structure and function of bone will provide a platform for bone-related biomedical research. Hydroxyapatite (HA), a bioactive ceramic material, has a similar structure and composition to bone mineralization products. In this study, we used HA as a microfluidic chip component to provide a highly bionic bone environment. HA substrates with different microchannel structures were printed by using ceramic stereolithography (SLA) technology, and the minimum trench width was 50 μm. The HA substrate with microchannels was sealed by a thin polydimethylsiloxane (PDMS) layer to make a HA-PDMS microfluidic chip. Cell culture experiments demonstrated that compared with PDMS, HA was more conducive to the proliferation and osteogenic differentiation of the human foetal osteoblast cell line (hFOB). In addition, the concentration gradient of the model drug doxorubicin hydrochloride (DOX) was successfully generated on a Christmas tree structure HA-PDMS chip, and the half maximal inhibitory concentration (IC50) of DOX was determined. The findings of this study indicate that the HA-PDMS microfluidic chip has great potential in the field of high-throughput bone-related drug screening and bone-related research.

Paper and pseudo-paper based flexible membrane devices

<p indent=0mm>With unique advantages of thin, porous, flexible, flammable and affordable, paper has been widely used in our daily life. Early in the 19th century, paper was first applied in biochemical analysis. Since then, paper had been used as a unique analytical platform. Paper-based analysis devices are easy to use, cheap, portable and disposable, thus they are widely considered as platform for POCT (point-of-care testing) and on-site detection. Liquid can automatically transport in paper cellulose networks without external pumps or energy, thus do not require extra instruments. The large specific surface area of fiber networks are ideal places for storing testing bio-chemical substances. Paper is also flexible and easy to fold together to form multilayer substrates of 3D chips, make it suitable for 3D cell culture and building multifunctional microfluidic chips. Meanwhile, paper-based analysis devices also have restrictions as chaos porous structure of the fibers interferes the optical signals and nonspecific adsorbs the testing samples, leading a low sensitivity of detection based on colorimetric. Due to the roughness of the fibers, it is still difficult to process the paper with high precision. In order to solve this, new types of paper (pseudo-paper) have emerged. In addition to biochemical analysis, paper also shows great prospect in the field of microelectronics. Currently, paper-based materials have been widely used in fields of flexible electronic devices, for example electronic circuits and energy storage devices. Paper exhibits piezoelectric behavior and is porous, degradable, make it promising materials in fabricating flexible electronics, display, soft robots and energy storage devices. Recently, enormous paper-based and pseudo-paper devices have been reported by researchers in various fields. These devices focus on the construction of new cost-effective microfluidics and electronics. The combination of paper-based microfluidic devices and electronic devices promotes the development of artificial skin, soft robots and flexible electronics. Considerable breakthroughs of new highly integrated paper-based chips have been achieved. In order to summarize the modern developing of paper and pseudo-paper devices and inspire scientists in various research fields, we present here an overall review that focuses on the historical developments to recent advances and future prospects of paper-based and pseudo-paper devices. These aspects include the preparation methods, the manipulation of microfluidics and electrons and multiple applications based on such manipulation. We hope that this review will promote the development of paper devices in various research fields such as analytical chemistry, materials science and electronic science.

An analytical model for void-free priming of microcavities

The present work deals with the microfluidic evolution of capillary surfaces that are formed during the priming of microcavity structures with a non-wetting liquid. Due to the large contact angle of the priming liquid, a trapping of air within the microcavities poses a major impediment to a complete filling. We tackle this issue by developing a two-dimensional analytical model describing the geometrical shape of capillary surfaces formed in microcavity structures. In particular, the model is employed to derive two quantitative conditions for a void-free priming of a microcavity structure in terms of its aspect ratio, rounding parameters and the channel width. Microfluidic experiments are performed to verify the analytical results. Finally, we make use of the model to demonstrate a pressure-driven aliquoting of a non-wetting sample liquid in a flow chamber with an array of 55 microcavities by introducing a second immiscible liquid acting as a sealant. In this way, our work constitutes a basis for the design of microcavity-based liquid aliquoting structures that are used in various fields of application like PCR arrays, cell culture chips or digital reaction arrays.