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Strong, stretchable, and durable biomaterials with shape memory properties can be useful in different biomedical devices, tissue engineering, and soft robotics. However, it is challenging to combine these features. Semi‐crystalline polyvinyl alcohol (PVA) has been used to make hydrogels by conventional methods such as freeze–thaw and chemical crosslinking, but it is formidable to produce strong materials with adjustable properties. Herein, a method to induce crystallinity and produce physically crosslinked PVA hydrogels via applying high‐concentration sodium hydroxide into dense PVA polymer is introduced. Such a strategy enables the production of physically crosslinked PVA biomaterial with high mechanical properties, low water content, resistance to injury, and shape memory properties. It is also found that the developed PVA hydrogel can recover 90% of plastic deformation due to extension upon supplying water, providing a strong contraction force sufficiently to lift objects 1100 times more than their weight. Cytocompatibility, antifouling property, hemocompatibility, and biocompatibility are also demonstrated in vitro and in vivo. The fabrication methods of PVA‐based catheters, injectable electronics, and microfluidic devices are demonstrated. This gelation approach enables both layer‐by‐layer and 3D printing fabrications. [ABSTRACT FROM AUTHOR]

The analysis of tear constituents at point-of-care settings has a potential for early diagnosis of ocular disorders such as dry eye disease, low-cost screening, and surveillance of at-risk subjects. However, current minimally-invasive rapid tear analysis systems for point-of-care settings have been limited to assessment of osmolarity or inflammatory markers and cannot differentiate between dry eye subclassifications. Here, we demonstrate a portable microfluidic system that allows quantitative analysis of electrolytes in the tear fluid that is suited for point-of-care settings. The microfluidic system consists of a capillary tube for sample collection, a reservoir for sample dilution, and a paper-based microfluidic device for electrolyte analysis. The sensing regions are functionalized with fluorescent crown ethers, o-acetanisidide, and seminaphtorhodafluor that are sensitive to mono- and divalent electrolytes, and their fluorescence outputs are measured with a smartphone readout device. The measured sensitivity values of Na+, K+, Ca2+ ions and pH in artificial tear fluid were matched with the known ion concentrations within the physiological range. The microfluidic system was tested with samples having different ionic concentrations, demonstrating the feasibility for the detection of early-stage dry eye, differential diagnosis of dry eye sub-types, and their severity staging. [ABSTRACT FROM AUTHOR]

We have designed and fabricated a miniature microscope from off-the-shelf components and a webcam, with built-in fluorescence capability for biomedical applications. The mini-microscope was able to detect both biochemical parameters, such as cell/tissue viability (e.g. live/dead assay), and biophysical properties of the microenvironment such as oxygen levels in microfabricated tissues based on an oxygen-sensitive fluorescent dye. This mini-microscope has adjustable magnifications from 8–60×, achieves a resolution as high as ＜2 μm, and possesses a long working distance of 4.5 mm (at a magnification of 8×). The mini-microscope was able to chronologically monitor cell migration and analyze beating of microfluidic liver and cardiac bioreactors in real time, respectively. The mini-microscope system is cheap, and its modularity allows convenient integration with a wide variety of pre-existing platforms including, but not limited to, cell culture plates, microfluidic devices, and organs-on-a-chip systems. Therefore, we envision its widespread application in cell biology, tissue engineering, biosensing, microfluidics, and organs-on-chips, which can potentially replace conventional bench-top microscopy where long-term in situ and large-scale imaging/analysis is required. [ABSTRACT FROM AUTHOR]

Precise control of media delivery to cells in microfluidic systems in a simple and efficient manner is a challenge for a number of cell-based applications. Conventional syringe pumps can deliver culture media into microfluidic devices at precisely controlled flow rates, but they are bulky and require a power source. On the other hand, passive microflow-generating systems cannot maintain continuous, controllable and long-term delivery of media. We have developed an on-chip microflow control technology that combines flow rate control and passive, long-term delivery of media to microwell tissue culture chambers. Here, a passive flow is initiated using the siphon effect and a yarn flow resistor is used to regulate the flow rate in the microchannel. Using the yarn flow resistor, the medium flow rate into the microfluidic cell culture system is made adjustable to a few hundred microliters per hour. To evaluate the effects of controlled flow on microfluidic cell culture properties (feasibility test), we measured the cell alignment and cytoskeletal arrangement of endothelial cells cultured in a microwell array inside the microfluidic channel. [ABSTRACT FROM AUTHOR]

The article discusses research studies on labs on a chip. Topics discussed include long-term sample preservation on-chip; wireless nanobiosensors using CMOS (complementary metal-oxide-semiconductor) chips; and attomolar DNA detection using nanotextured electrodes. It also discusses the need for point-of-care lab-on-a-chip devices and diagnostic chips for use in remote areas.

Cell alignment is a critical factor to govern cellular behavior and function for various tissue engineering applications ranging from cardiac to neural regeneration. In addition to physical geometry, strain is a crucial parameter to manipulate cellular alignment for functional tissue formation. In this paper, we introduce a simple approach to generate a range of gradient static strains without external mechanical control for the stimulation of cellular behavior within 3D biomimetic hydrogel microenvironments. A glass-supported microfluidic chip with a convex flexible polydimethylsiloxane (PDMS) membrane on the top was employed for loading the cells suspended in a prepolymer solution. Following UV crosslinking through a photomask with a concentric circular pattern, the cell-laden hydrogels were formed in a height gradient from the center (maximum) to the boundary (minimum). When the convex PDMS membrane retracted back to a flat surface, it applied compressive gradient forces on the cell-laden hydrogels. The concentric circular hydrogel patterns confined the direction of hydrogel elongation, and the compressive strain on the hydrogel therefore resulted in elongation stretch in the radial direction to guide cell alignment. NIH3T3 cells were cultured in the chip for 3 days with compressive strains that varied from ~65% (center) to ~15% (boundary) on hydrogels. We found that the hydrogel geometry dominated the cell alignment near the outside boundary, where cells aligned along the circular direction, and the compressive strain dominated the cell alignment near the center, where cells aligned radially. This study developed a new and simple approach to facilitate cellular alignment based on hydrogel geometry and strain stimulation for tissue engineering applications. This platform offers unique advantages and is significantly different from the existing approaches owing to the fact that gradient generation was accomplished in a miniature device without using an external mechanical source. [ABSTRACT FROM AUTHOR]

The article cites several research studies on attomolar detection with microfluidic enzyme-linked immunosorbent assays (ELISA). A study demonstrated that actuatable microwell patterned microfluidic chip was capable of performing ELISA assays with smaller volumes with a low limit of detection. Topics discussed include highly tunable plasmofluidic lens and microfluidic membrane-assisted co-culture system.

The article discusses research related to the use of microfluidic devices in chemistry and biologica laboratories. A study which performs cytotoxicity testing of graphene oxide (GO) sheets, multi-wall carbon nanotubes (MWCNTs), and CdSe nanoparticles found negligible cytotoxicity for GO. Another study which examines the microscale structures on rice leaves revealed that liquids with a lower surface tension than water could not preserve their shape on the surface of a rice leaf.

The research areas of tissue engineering and drug development have displayed increased interest in organ-on-a-chip studies, in which physiologically or pathologically relevant tissues can be engineered to test pharmaceutical candidates. Microfluidic technologies enable the control of the cellular microenvironment for these applications through the topography, size, and elastic properties of the microscale cell culture environment, while delivering nutrients and chemical cues to the cells through continuous media perfusion. Traditional materials used in the fabrication of microfluidic devices, such as poly(dimethylsiloxane) (PDMS), offer high fidelity and high feature resolution, but do not facilitate cell attachment. To overcome this challenge, we have developed a method for coating microfluidic channels inside a closed PDMS device with a cell-compatible hydrogel layer. We have synthesized photocrosslinkable gelatin and tropoelastin-based hydrogel solutions that were used to coat the surfaces under continuous flow inside 50 μm wide, straight microfluidic channels to generate a hydrogel layer on the channel walls. Our observation of primary cardiomyocytes seeded on these hydrogel layers showed preferred attachment as well as higher spontaneous beating rates on tropoelastin coatings compared to gelatin. In addition, cellular attachment, alignment and beating were stronger on 5% (w/v) than on 10% (w/v) hydrogel-coated channels. Our results demonstrate that cardiomyocytes respond favorably to the elastic, soft tropoelastin culture substrates, indicating that tropoelastin-based hydrogels may be a suitable coating choice for some organ-on-a-chip applications. We anticipate that the proposed hydrogel coating method and tropoelastin as a cell culture substrate may be useful for the generation of elastic tissues, e.g. blood vessels, using microfluidic approaches. [ABSTRACT FROM AUTHOR]

The article discusses research on chemistry and biology. Topics discussed include a study by Marie et al, on a fluidic platform that offers advantages over current state-of-the-art sequencing technologies, a study by A. T. Ciftlik et al, which focused on the development of a microfluidic tissue processor (MTP) and a study by V. Shkolnikov and J. G. Santiago on the development of the species-altered flourescence imaging (SAFI).

Heterotypic functional materials with compositional and topographical properties that vary spatiotemporally on the micro- or nanoscale are common in nature. However, fabricating such complex materials in the laboratory remains challenging. Here we describe a method to continuously create microfibres with tunable morphological, structural and chemical features using a microfluidic system consisting of a digital, programmable flow control that mimics the silk-spinning process of spiders. With this method we fabricated hydrogel microfibres coded with varying chemical composition and topography along the fibre, including gas micro-bubbles as well as nanoporous spindle-knots and joints that enabled directional water collection. We also explored the potential use of the coded microfibres for tissue engineering applications by creating multifunctional microfibres with a spatially controlled co-culture of encapsulated cells. [ABSTRACT FROM AUTHOR]

Delivery of nutrients and oxygen within three-dimensional (3D) tissue constructs is important to maintain cell viability. We built 3D cell-laden hydrogels to validate a new tissue perfusion model that takes into account nutrition consumption. The model system was analyzed by simulating theoretical nutrient diffusion into cell-laden hydrogels. We carried out a parametric study considering different microchannel sizes and inter-channel separation in the hydrogel. We hypothesized that nutrient consumption needs to be taken into account when optimizing the perfusion channel size and separation. We validated the hypothesis by experiments. We fabricated circular microchannels ( r = 400 μm) in 3D cell-laden hydrogel constructs ( R = 7.5 mm, volume = 5 ml). These channels were positioned either individually or in parallel within hydrogels to increase nutrient and oxygen transport as a way to improve cell viability. We quantified the spatial distribution of viable cells within 3D hydrogel scaffolds without channels and with single- and dual-perfusion microfluidic channels. We investigated quantitatively the cell viability as a function of radial distance from the channels using experimental data and mathematical modeling of diffusion profiles. Our simulations show that a large-channel radius as well as a large channel to channel distance diffuse nutrients farther through a 3D hydrogel. This is important since our results reveal that there is a close correlation between nutrient profiles and cell viability across the hydrogel. [ABSTRACT FROM AUTHOR]

The ability to rapidly generate concentration gradients of diffusible molecules has important applications in many chemical and biological studies. Here we established spatially and temporally controllable concentration gradients of molecules (i.e.proteins or toxins) in a portable microfluidic device in an easy and rapid manner. The formation of the concentration gradients was initiated by a passive-pump-induced forward flow and further optimized during an evaporation-induced backward flow. The centimeter-long gradients along the microfluidic channel were shown to be spatially and temporally controlled by the backward flow. The gradient profile was stabilized by stopping the flow. Computational simulations of this dynamic process illustrated the combined effects of convection and diffusion on the gradient generation, and fit well with the experimental data. To demonstrate the applications of this methodology, a stabilized concentration gradient of a cardiac toxin, alpha-cypermethrin, along the microchannel was used to test the response of HL-1 cardiac cells in the micro-device, which correlated with toxicity data obtained from multi-well plates. The approach presented here may be useful for many biological and chemical processes that require rapid generation of long-range gradients in a portable microfluidic device. [ABSTRACT FROM AUTHOR]

Highlights: [•] Heart-on-a-chip for cardiac drug development. [•] Microfluidic devices mimicking the lung structure help generate disease models. [•] Microfluidic tissue engineering leads to functional intestine models in vitro. [Copyright &y& Elsevier]

Recently, there has been an increasing effort in developing new fabrication methods for rapid prototyping of microfluidic chips using thermoplastic materials. This is mainly due to the excellent properties of thermoplastics including inherent robustness to mechanical deformation and resistance to chemicals. In this paper, we report on the development of a novel rapid prototyping method to fabricate microfluidic chips from thermoplastic materials with embedded pneumatic controls. A CO 2 laser micromachining method was employed to engrave and cut poly(methyl methacrylate) (PMMA) sheets, which together with a thermoplastic polyurethane (TPU) film, enabled fabrication of various functional microfluidic elements including microvalves, micropumps, and bioreactors. To generate the gas-actuated microvalve, unfocused CO 2 laser beam was used to fabricate semi-circular fluid channels in PMMA. An optimized chemical surface treatment procedure was subsequently applied to smoothen the surface of the microchannels. TPU film serving as a flexible membrane was attached above the semi-circular channel sandwiched by another piece of PMMA containing a gas channel to achieve the architecture of the microvalve. A thermal fusion bonding method was developed to bond TPU film to the PMMA components in a single step. A peristaltic micropump was also fabricated consisting of sequential interconnected gas-actuated microvalves. In addition, results from cell cultures in fabricated whole-thermoplastic bioreactors demonstrated biocompatibility of the whole-thermoplastic microchips. Taken together, the developed fabrication process in conjunction with proposed thermoplastic materials provide an inexpensive and versatile method for rapid prototyping of various microfluidic devices. [ABSTRACT FROM AUTHOR]

Engineering cardiac tissues and organ models remains a great challenge due to the hierarchical structure of the native myocardium. The need of integrating blood vessels brings additional complexity, limiting the available approaches that are suitable to produce integrated cardiovascular organoids. In this work we propose a novel hybrid strategy based on 3D bioprinting, to fabricate endothelialized myocardium. Enabled by the use of our composite bioink, endothelial cells directly bioprinted within microfibrous hydrogel scaffolds gradually migrated towards the peripheries of the microfibers to form a layer of confluent endothelium. Together with controlled anisotropy, this 3D endothelial bed was then seeded with cardiomyocytes to generate aligned myocardium capable of spontaneous and synchronous contraction. We further embedded the organoids into a specially designed microfluidic perfusion bioreactor to complete the endothelialized-myocardium-on-a-chip platform for cardiovascular toxicity evaluation. Finally, we demonstrated that such a technique could be translated to human cardiomyocytes derived from induced pluripotent stem cells to construct endothelialized human myocardium. We believe that our method for generation of endothelialized organoids fabricated through an innovative 3D bioprinting technology may find widespread applications in regenerative medicine, drug screening, and potentially disease modeling. [ABSTRACT FROM AUTHOR]

In the past decade, significant advances have been made in the design and optimization of novel biomaterials and microfabrication techniques to generate vascularized tissues. Novel microfluidic systems have facilitated the development and optimization of in vitro models for exploring the complex pathophysiological phenomena that occur inside a microvascular environment. To date, most of these models have focused on engineering of increasingly complex systems, rather than analyzing the molecular and cellular mechanisms that drive microvascular network morphogenesis and remodeling. In fact, mutual interactions among endothelial cells (ECs), supporting mural cells and organ-specific cells, as well as between ECs and the extracellular matrix, are key driving forces for vascularization. This review focuses on the integration of materials science, microengineering and vascular biology for the development of in vitro microvascular systems. Various approaches currently being applied to study cell-cell/cell-matrix interactions, as well as biochemical/biophysical cues promoting vascularization and their impact on microvascular network formation, will be identified and discussed. Finally, this review will explore in vitro applications of microvascular systems, in vivo integration of transplanted vascularized tissues, and the important challenges for vascularization and controlling the microcirculatory system within the engineered tissues, especially for microfabrication approaches. It is likely that existing models and more complex models will further our understanding of the key elements of vascular network growth, stabilization and remodeling to translate basic research principles into functional, vascularized tissue constructs for regenerative medicine applications, drug screening and disease models. [ABSTRACT FROM AUTHOR]

Continual monitoring of secreted biomarkers from organ-on-a-chip models is desired to understand their responses to drug exposure in a noninvasive manner. To achieve this goal, analytical methods capable of monitoring trace amounts of secreted biomarkers are of particular interest However, a majority of existing biosensing techniques suffer from limited sensitivity, selectivity, stability, and require large working volumes, especially when cell culture medium is involved, which usually contains a plethora of nonspecific binding proteins and interfering compounds. Hence, novel analytical platforms are needed to provide noninvasive, accurate information on the status of organoids at low working volumes. Here, we report a novel microfluidic aptamer-based electrochemical biosensing platform for monitoring damage to cardiac organoids. The system is scalable, low-cost, and compatible with microfluidic platforms easing its integration with microfluidic bioreactors. T o create the creatine kinase (CK)-MB biosensor, the microelectrode was functionalized with aptamers that are specific to CK-MB biomarker secreted from a damaged cardiac tissue. Compared to antibody-based sensors, the proposed aptamer-based system was highly sensitive, selective, and stable. The performance of the sensors was assessed using a heart-on-a-chip system constructed from human embryonic stem cell-derived cardiomyocytes following exposure to a cardiotoxic drug, doxorubicin. The aptamer-based biosensor was capable of measuring trace amounts of CKMB secreted by the cardiac organoids upon drug treatments in a dose-dependent manner, which was in agreement with the beating behavior and cell viability analyses. We believe that, our microfluidic electrochemical biosensor using aptamer-based capture mechanism will find widespread applications in integration with organ-on-a-chip platforms for in situ detection of biomarkers at low abundance and high sensitivity. [ABSTRACT FROM AUTHOR]

Novel microfluidic tools allow new ways to manufacture and test drug delivery systems. Organ-on-a-chip systems — microscale recapitulations of complex organ functions — promise to improve the drug development pipeline. This review highlights the importance of integrating microfluidic networks with 3D tissue engineered models to create organ-on-a-chip platforms, able to meet the demand of creating robust preclinical screening models. Specific examples are cited to demonstrate the use of these systems for studying the performance of drug delivery vectors and thereby reduce the discrepancies between their performance at preclinical and clinical trials. We also highlight the future directions that need to be pursued by the research community for these proof-of-concept studies to achieve the goal of accelerating clinical translation of drug delivery nanoparticles. [ABSTRACT FROM AUTHOR]

Engineered surface-bound moleculargradients are of great importancefor a range of biological applications. In this paper, we fabricateda polydopamine gradient on a hydrophobic surface. A microfluidic devicewas used to generate a covalently conjugated gradient of polydopamine(PDA), which changed the wettabilty and the surface energy of thesubstrate. The gradient was subsequently used to enable the spatialdeposition of adhesive proteins on the surface. When seeded with humanadipose mesenchymal stem cells, the PDA-graded surface induced a gradientof cell adhesion and spreading. The PDA gradient developed in thisstudy is a promising tool for controlling cellular behavior and maybe useful in various biological applications. [ABSTRACT FROM AUTHOR]

The article offers information related to lab on a chip. It relates the studies by S. G. Ricoult and colleagues, H. Onoe and colleagues, and R. W. Muthard and S. L. Diamond. Topics discussed in the studies are the low-cost nanoprinting of proteins, the use of innovative technique as cell delivery vehicles and building blocks for tissue engineering, and the development of microfluidic device to facilitate orthogonal control over shear stress and pressure at the site of thrombus formation.

In this paper, we report a method to fabricate microengineered hydrogels that contain a concentration gradient of a drug for high-throughput analysis of cell-drug interactions. A microfluidic gradient generator was used to create a concentration gradient of okadaic acid (OA) as a model drug within poly(ethylene glycol) diacrylate hydrogels. These hydrogels were then incubated with MC3T3-E1 cell seeded glass slides to investigate the cell viability through the spatially controlled release of OA. The drug was released from the hydrogel in a gradient manner and induced a gradient of the cell viability. The drug concentration gradient containing hydrogels developed in this study have the potential to be used for drug discovery and diagnostics applications due to their ability to simultaneously test the effects of different concentrations of various chemicals. [ABSTRACT FROM AUTHOR]

We describe a microfluidic device for generating nonlinear (exponential and sigmoidal) concentration gradients, coupled with a microwell array for cell storage and analysis. The device has two inputs for coflowing multiple aqueous solutions, a main coflow channel and an asymmetrical grid of fluidic channels that allows the two solutions to combine at intersection points without fully mixing. Due to this asymmetry and diffusion of the two species in the coflow channel, varying amounts of the two solutions enter each fluidic path. This induces exponential and sigmoidal concentration gradients at low and high flow rates, respectively, making the microfluidic device versatile. A key feature of this design is that it is space-saving, as it does not require multiplexing or a separate array of mixing channels. Furthermore, the gradient structure can be utilized in concert with cell experiments, to expose cells captured in microwells to various concentrations of soluble factors. We demonstrate the utility of this design to assess the viability of fibroblast cells in response to a range of hydrogen peroxide (H2O2) concentrations. [ABSTRACT FROM AUTHOR]

Abstract: This study describes a novel method for generation of an array of three-dimensional (3D) multicellular spheroids within a microchannel in patterned cultures containing one or multiple cell types. This method uses a unique property of a cross-linked albumin coated surface in which the surface can be switched from non-adhesive to cell adhesive upon electrostatic adsorption of a polycation. Introduction of a solution containing albumin and a cross-linking agent into a microchannel with an array of microwells caused the entire surface, with the exception of the interior of the microwells, to become coated with the cross-linked albumin layer. Cells that were seeded within the microchannel did not adhere to the surface of the microchannel and became entrapped in the microwells. HepG2 cells seeded in the microwells formed 3D spheroids with controlled sizes and shapes depending upon the dimensions of the microwells. When the albumin coated surface was subsequently exposed to an aqueous solution containing poly(ethyleneimine) (PEI), adhesion of secondary cells, fibroblasts, occurred in the regions surrounding the arrayed spheroids. This coculture system can be coupled with spatially controlled fluids such as gradients and focused flow generators for various biological and tissue engineering applications. [ABSTRACT FROM AUTHOR]

Abstract: The cellular microenvironment plays an integral role in improving the function of microengineered tissues. Control of the microarchitecture in engineered tissues can be achieved through photopatterning of cell-laden hydrogels. However, despite high pattern fidelity of photopolymerizable hydrogels, many such materials are not cell-responsive and have limited biodegradability. Here, we demonstrate gelatin methacrylate (GelMA) as an inexpensive, cell-responsive hydrogel platform for creating cell-laden microtissues and microfluidic devices. Cells readily bound to, proliferated, elongated, and migrated both when seeded on micropatterned GelMA substrates as well as when encapsulated in microfabricated GelMA hydrogels. The hydration and mechanical properties of GelMA were demonstrated to be tunable for various applications through modification of the methacrylation degree and gel concentration. The pattern fidelity and resolution of GelMA were high and it could be patterned to create perfusable microfluidic channels. Furthermore, GelMA micropatterns could be used to create cellular micropatterns for in vitro cell studies or 3D microtissue fabrication. These data suggest that GelMA hydrogels could be useful for creating complex, cell-responsive microtissues, such as endothelialized microvasculature, or for other applications that require cell-responsive microengineered hydrogels. [Copyright &y& Elsevier]