Lithographic Microneedle-Motors from Multimodal Microfluidics for Cargo Delivery.

Micromotors have led to an unprecedented revolution in the field of cargo delivery. Attempts in this area trend toward enriching their structures and improving their functions to promote their further applications. Herein, novel microneedle-motors (MNMs) for active drug delivery through a flexible multimodal microfluidic lithographic approach are presented. The multimodal microfluidics is composed of a co-flow geometry-derived droplet fluid and an active cargo mixed laminar flow in a triangular microchannel. The MNMs with sharp tips and spherical fuel-loading cavities are obtained continuously from microfluidics with the assistance of flow lithography. The structural parameters of the MNMs could be precisely tailored by simply choosing the flow speed or the shape of the photomask. As the actives are mixed into the phase solution during the generation, the resultant MNMs are loaded with cargoes for direct applications without any extra complex operation. Based on these features, it is demonstrated that with sharp tips and autonomous movement, the MNMs can efficiently penetrate the tissue-like substrates, indicating the potential in overcoming physiological barriers for cargo release. These results indicate that the proposed multimodal microfluidic lithographic MNMs are valuable for practical active cargo delivery in biomedical and other relative areas.

Scalable Production of Biomedical Microparticles via High-Throughput Microfluidic Step Emulsification.

Drug microcarriers are widely used in disease treatment, and microfluidics is well established in the preparation of microcarrier particles. A proper design of the microfluidic platform toward scalable production of drug microcarriers can extend its application values in wound healing, where large numbers of microcarriers are required. Here, a microfluidic step emulsification method for the preparation of monodisperse droplets is presented. The droplet size depends primarily on the microchannel depth rather than flow rate, making the system robust for high-throughput production of droplets and hydrogel microparticles. Based on this platform, basic fibroblast growth factor (bFGF) is uniformly encapsulated in the microparticles, and black phosphorus (BP) is incorporated for controllable release via near-infrared (NIR) stimulation. The microparticles serve as drug carriers to be applied to the wound site, inducing angiogenesis and collagen deposition, thereby accelerating wound repair. These results indicate that the step emulsification technique provides a promising solution to scalable production of drug microcarriers for wound healing as well as tissue regeneration.

Noninvasive Multiplexed Analysis of Bladder Cancer-Derived Urine Exosomes via Janus Magnetic Microspheres.

Bladder cancer greatly endangers human health, and its early diagnosis is of vital importance. Exosomes, which contain proteins and nucleic acids related to their source cells, are expected to be an emerging biomarker for bladder cancer detection. Here, we propose a novel system for multiplexed analysis of bladder cancer-derived urine exosomes based on Janus magnetic microspheres as barcoded microcarriers. The microcarriers are constructed by droplet-templated coassembly of colloidal silica nanoparticles and magnetic nanoparticles under a magnetic field. The microcarriers possess one hemisphere with structural color and the other hemisphere with magneto-responsiveness. Benefiting from the unique structure, these Janus microcarriers could serve as barcodes and could move controllably in a sample solution, thus realizing the multiplex detection of exosomes with high sensitivity. Notably, the present platform is noninvasive since a urine specimen, as an ideal source of bladder cancer-derived exosomes, is employed as the sample solution. This feature, together with the good sensitivity, specificity, low sample consumption, and easy operation, indicates the great potential of the platform for bladder cancer diagnosis in clinical applications.

Multifunctional Inverse Opal Microneedle Arrays for Drug Delivery and Monitoring.

Microneedle arrays (MNs) have a demonstrated value in transdermal drug delivery systems. Attempts to this technology focus on the generation of functional MNs to achieve intelligent drug delivery. Here, multifunctional inverse opal microneedle (IOMN) arrays with the abilities are reported to load various drugs and monitor drug release. The IOMNs are generated by using poly(ethylene glycol) diacrylate (PEGDA) to replicate hierarchical structure templates that are composed of self-assembled silica colloidal nanoparticles in the inverted cone structure wells. Because of their interconnected porous structures, different actives, or drugs can be loaded into the IOMNs without organic solvents and chemical polymerization. It is demonstrated that when these drugs loaded IOMNs pierce the skin at position of interest and for slow release, the average refractive index of the IOMNs decreases with the release process, resulting in a corresponding blueshift of their characteristic spectrum. Thus, by measuring the wavelength shift value of the IOMNs, the amount of released drugs can be monitored, providing essential guidance for efficient clinical treatment. These features indicate that the IOMNs are valuable smart drug delivery systems in personalized therapy.

Biomimetic Anticoagulated Porous Particles with Self-Reporting Structural Colors.

Anticoagulation is vital to maintain blood fluidic status and physiological functions in the field of clinical blood-related procedures. Here, novel biomimetic anticoagulated porous inverse opal hydrogel particles is presented as anticoagulant bearing dynamic screening capability. The inverse opal hydrogel particles possess abundant sulfonic and carboxyl groups, which serve as binding sites with multiple coagulation factors and inhibit the blood coagulation process. Owing to the variations of refractive index and pore sizes during the binding process, the particles appeared corresponding structure color variations, which can be adopted as sensory index of anticoagulation. Based on these features, a sensor containing these diverse structure color particle units is constructed for pattern recognition of coagulation factors level in clinical plasma samples. By analyzing the sensory information of the unit, the colorimetric "fingerprint" for each target can be obtained and summarized as a database. Besides, a portable test-strip integrating sensory units is developed to distinguish the sample regarding abnormal coagulation factors-derived diseases via multivariate data analysis. It is believed that such biomimetic anticoagulated structural color particles and their derived sensor will open new avenue for clinical detection and disease diagnosis.

Biomimetic hepatic lobules from three-dimensional imprinted cell sheets.

Liver-tissue engineering has proven valuable in treating liver diseases, but the construction of liver tissues with high fidelity remains challenging. Here, we present a novel three-dimensional (3D)-imprinted cell-sheet strategy for the synchronous construction of biomimetic hepatic microtissues with high accuracy in terms of cell type, density, and distribution. To achieve this, the specific composition of hepatic cells in a normal human liver was determined using a spatial proteogenomics dataset. The data and biomimetic hepatic micro-tissues with hexagonal hollow cross-sections indicate that cell information was successfully generated using a homemade 3D-imprinted device for layer-by-layer imprinting and assembling the hepatic cell sheets. By infiltrating vascular endothelial cells into the hollow section of the assembly, biomimetic hepatic microtissues with vascularized channels for nutrient diffusion and drug perfusion can be obtained. We demonstrate that the resultant vascularized biomimetic hepatic micro-tissues can not only be integrated into a microfluidic drug-screening liver-on-a-chip but also assembled into an enlarged physiological structure to promote liver regeneration. We believe that our 3D-imprinted cell sheets strategy will open new avenues for biomimetic microtissue construction.

Developing organs-on-chips for biomedical applications.

In recent years, organs-on-chips have been arousing great interest for their bionic and stable construction of crucial human organs in vitro. Compared with traditional animal models and two-dimensional cell models, organs-on-chips could not only overcome the limitations of species difference and poor predict ability but also be capable of reappearing the complex cell-cell interaction, tissue interface, biofluid and other physiological conditions of humans. Therefore, organs-on-chips have been regarded as promising and powerful tools in diverse fields such as biology, chemistry, medicine and so on. In this perspective, we present a review of organs-on-chips for biomedical applications. After introducing the key elements and manufacturing craft of organs-on-chips, we intend to review their cut-edging applications in biomedical fields, incorporating biological analysis, drug development, robotics and so on. Finally, the emphasis is focused on the perspectives of organs-on-chips.

Engineered stem cells by emerging biomedical stratagems.

Stem cell therapy holds immense potential as a viable treatment for a widespread range of intractable disorders. As the safety of stem cell transplantation having been demonstrated in numerous clinical trials, various kinds of stem cells are currently utilized in medical applications. Despite the achievements, the therapeutic benefits of stem cells for diseases are limited, and the data of clinical researches are unstable. To optimize tthe effectiveness of stem cells, engineering approaches have been developed to enhance their inherent abilities and impart them with new functionalities, paving the way for the next generation of stem cell therapies. This review offers a detailed analysis of engineered stem cells, including their clinical applications and potential for future development. We begin by briefly introducing the recent advances in the production of stem cells (induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs)). Furthermore, we present the latest developments of engineered strategies in stem cells, including engineered methods in molecular biology and biomaterial fields, and their application in biomedical research. Finally, we summarize the current obstacles and suggest future prospects for engineered stem cells in clinical translations and biomedical applications.

Rotary Structural Color Spindles from Droplet Confined Magnetic Self-Assembly.

Structural colors materials are profoundly explored owing to their fantastic optical properties and widespread applications. Development of structural color materials bearing flexible morphologies and versatile functionalities is highly anticipated. Here, a droplet-confined, magnetic-induced self-assembly strategy for generating rotary structural color spindles (SCSPs) by fast solvent extraction is proposed. The as-prepared SCSPs exhibit an orderly close-packed lattice structure, thus appearing brilliant structural colors that serve as encoding tags for multiplexed bioassays. Besides, benefitting from the abundant specific surface area, biomarkers can be labeled on the SCSPs with high efficiency for specific detection of analytes in clinical samples. Moreover, the directional magnetic moment arrangement enables contactless magnetic manipulation of the SCSPs, and the resultant rotary motions of the SCSPs generates turbulence in the detection solution, thus significantly improving the detection efficiency and shortening the detection time. Based on these merits, a portable point-of-care-testing strip integrating the rotary SCSPs is further constructed and the capability and advantages of this platform for multiplexed detection of tumor-related exosomes in clinical samples are demonstrated. This study offers a new way for the control of bottom-up self-assembly and extends the configuration and application values of colloidal crystal structural colors materials.

Sensors-integrated organ-on-a-chip for biomedical applications.

As a promising new micro-physiological system, organ-on-a-chip has been widely utilized for in vitro pharmaceutical study and tissues engineering based on the three-dimensional constructions of tissues/organs and delicate replication of in vivo-like microenvironment. To better observe the biological processes, a variety of sensors have been integrated to realize in-situ, real-time, and sensitive monitoring of critical signals for organs development and disease modeling. Herein, we discuss the recent research advances made with respect to sensors-integrated organ-on-a-chip in this overall review. Firstly, we briefly explore the underlying fabrication procedures of sensors within microfluidic platforms and several classifications of sensory principles. Then, emphasis is put on the highlighted applications of different types of organ-on-a-chip incorporated with various sensors. Last but not least, perspective on the remaining challenges and future development of sensors-integrated organ-on-a-chip are presented.

Magnetic photonic crystals for biomedical applications.

Magnetic photonic crystals (PhCs), as a representative responsive structural color material, have attracted increasing research focus due to merits such as brilliant refraction colors, instant responsiveness, and excellent manipuility, thus having been widely applied for color displaying, three-dimensional printing, sensing, and so on. Featured with traits such as contactless manner, flexible orientations, and adjustable intensity of external magnetism, magnetic PhCs have shown great superiority especially in the field of biomedical applications such as bioimaging and auxiliary clinical diagnosis. In this review, we summarize the current advancements of magnetic PhCs. We first introduce the fundamental principles and typical characteristics of PhCs. Afterward, we present several typical self-assembly strategies with their frontiers in practical applications. Finally, we analyze the current situations of magnetic PhCs and put forward the prospective challenges and future development directions.

Liquid Metal Droplets-Based Elastomers from Electric Toothbrush-Inspired Revolving Microfluidics.

Liquid metal (LM)-based elastomers have a demonstrated value in flexible electronics. Attempts in this area include the development of multifunctional LM-based elastomers with controllable morphology, superior mechanical performances, and great stability. Herein, inspired by the working principle of electric toothbrushes, a revolving microfluidic system is presented for the generation of LM droplets and construction of desired elastomers. The system involves revolving modules assembled by a needles array and 3D microfluidic channels. LM droplets can be generated with controllable size in a high-throughput manner due to the revolving motion-derived drag force. It is demonstrated that by employing a poly(dimethylsiloxane) (PDMS) matrix as the collection phase, the generated LM droplets can act as conductive fillers for the construction of flexible electronics directly. The resultant LM droplets-based elastomers exhibit high mechanical strength, stable electrical performance, as well as superior self-healing property benefiting from the dynamic exchangeable urea bond of the polymer matrix. Notably, due to the flexible programmable feature of the LM droplets embedded within the elastomers, various patterned LM droplets-based elastomers can be easily achieved. These results indicate that the proposed microfluidic LM droplets-based elastomers have a great potential for promoting the development of flexible electronics.

Biomimetic Enzyme Cascade Structural Color Hydrogel Microparticles for Diabetic Wound Healing Management.

Hard-healing diabetic wound brings burgeoning physical and mental burdens to patients. Current treatment strategies tend to achieve multistage promotion and real-time reporting to facilitate wound management. Herein, a biomimetic enzyme cascade inverse opal microparticles system for wound healing, which is intergated with glucose oxidase (GOD) and copper peroxide (CP). Such microparticles are composed of biofriendly hyaluronic acid methacryloyl (HAMA) and pH-responsive acrylic acid (AA), which provided abundant binding sites and spaces for chemical immobilizing and physical doping of enzymes and metal bioinorganics. When the cascade catalytic system is applied on wound sites, hyperglycemia environment would serve as a hydrogen peroxide (H2 O2 ) generator through GOD catalysis, while acidic environment triggers the decomposition of CP, further catalyzing H2 O2 to generate reactive oxygen species (ROS). Additionally, the distinctive structural color of the microparticles can visually reflect the wound pH and intelligently estimate the healing state. It is demonstrated that such microparticle systems exhibit excellent broad-spectrum antibacterial and angiogenesis-promoting properties, as well as significant real-time reporting ability for wound healing. These features indicate that enzyme cascade structural color microparticles possess valuable potential in wound healing and related field.

Aptamer-Functionalized Barcodes in Herringbone Microfluidics for Multiple Detection of Exosomes.

Tumor-derived exosomes are vital for clinical dynamic and accurate tumor diagnosis, thus developing sensitive and multiple exosomes detection technology has attracted remarkable attention of scientists. Here, a novel herringbone microfluidic device with aptamer-functionalized barcodes integration for specific capture and multiple detection of tumor-derived exosomes is presented. The barcodes with core-shell constructions are obtained by partially replicating the periodically ordered hexagonal close-packaged colloidal crystal beads. As their inverse opal hydrogel shell possesses rich interconnected pores, the barcodes could provide abundant surface area for functionalization of DNA aptamers to realize specific recognition of target exosomes. Besides, the encoded structure colors of the barcodes can be maintained stably during the detection events as their hardish cores are with sufficient mechanical strength. It is demonstrated that by embedding these barcodes in herringbone groove microfluidic device with designed patterns, the specific capture efficiency and synergetic detection of multiple tumor-derived exosomes in peripheral blood can be significantly improved due to enhanced resistance of turbulent flow. These features make the aptamer-functionalized barcodes and herringbone microfluidics integrated platform promising for exosomes extraction and dynamic tumor diagnosis.

Microfluidic technologies for cell deformability cytometry.

Microfluidic detection methods for cell deformability cytometry have been regarded as powerful tools for single-cell analysis of cellular mechanical phenotypes, thus having been widely applied in the fields of cell preparation, separation, clinical diagnostics and so on. Featured with traits like easy operations, low cost and high throughput, such methods have shown great potentials on investigating physiological state and pathological changes during cellular deformation. Herein, a review on the advancements of microfluidic-based cell deformation cytometry is presented. We discuss several representative microfluidic-based cell deformability cytometry methods with their frontiers in practical applications. Finally, we analyze the current status and propose the remaining challenges with future perspectives and development directions.

Structural Color Ionic Hydrogel Patches for Wound Management.

Ionic hydrogels have attracted extensive attention because of their wide applicability in electronic skins, biosensors, and other biomedical areas. Tremendous effort is dedicated to developing ionic hydrogels with improved detection accuracy and multifunctionality. Herein, we present an inverse opal scaffold-based structural color ionic hydrogel with the desired features as intelligent patches for wound management. The patches were composed of a polyacrylamide-poly(vinyl alcohol)-polyethylenimine-lithium chloride (PAM-PVA-PEI-LiCl) inverse opal scaffold and a vascular endothelial growth factor (VEGF) mixed methacrylated gelatin (GelMA) hydrogel filler surface. The scaffold imparted the composite patches with brilliant structural color, conductive property, and freezing resistance, while the VEGF-GelMA surface could not only prevent the ionic hydrogel from the interference of complex wound conditions but also contribute to the cell proliferation and tissue repair in the wounds. Thus, the hydrogel patches could serve as electronic skins for in vivo wound healing and monitoring with high accuracy and reliability. These features indicate that the proposed structural color ionic hydrogel patches have great potential for clinical applications.

Bioinspired Perovskite Nanocrystals-Integrated Photonic Crystal Microsphere Arrays for Information Security.

Information security occupies an important position in the era of big data. Attempts to improve the security performance tend to impart them with more additional encryption strategies. Herein, inspired by the wettability feature of Stenocara beetle elytra and signal model of traffic light, a novel array of perovskite nanocrystals (PNs)-integrated PhC microsphere for information security is presented. The photoluminescent PNs are encapsulated in angle-independent PhC microspheres to impart them with binary optical signals as coding information. Through the multimask superposition approach, PNs-integrated PhC microspheres with different codes are placed into fluorosilane-treated PDMS substrate to form different arrays. These arrays could converge moisture on PhC microspheres in wet environment, which avoids the ions loss of the PNs and effectively prevented mutual contamination. In addition, the fluorescence of the PNs inside PhC microspheres could reversibly quench or recover in response to the environmental moisture. Based on these features, it is demonstrated that the PNs-integrated PhC microsphere arrays could realize various information encryption modes, which indicate their excellent values in information security fields.

Bio-inspired shape-memory structural color hydrogel film.

Structural colors, derived from existing natural creatures, have aroused widespread attention in the materials regulation for different applications. Here, inspired by the color adjusting mechanism of hummingbird, we present a novel shape-memory structural color hydrogel film by introducing shape memory polymers (SMPs) into synthetic inverse opal scaffold structure. The excellent flexibility as well as the inverse opal structure of the hydrogel films imparts them with stable stretchability and brilliant structural colors. Benefiting from the transient structural anisotropy of copolymers, the hybrid films are possessed with shape-morphing behaviors capability. Based on the shape transformations and color responsiveness performance, we have demonstrated diverse structural color actuators with complex shapes for different tasks. Notably, as the photothermal responsive graphene quantum dots were integrated into the hydrogel, the hybrid films could also be endowed with the feature of light-controlled reversible deformation with synchronous structural color variation. These features demonstrate that the presented shape-memory structural color hydrogel film is valuable for soft robotics with multi-functions of sensing, communication and disguise.

Bio-Inspired Imprinting Materials for Biomedical Applications.

Inspired by the recognition mechanism of biological molecules, molecular imprinting techniques (MITs) are imparted with numerous merits like excellent stability, recognition specificity, adsorption properties, and easy synthesis processes, and thus broaden the avenues for convenient fabrication protocol of bio-inspired molecularly imprinted polymers (MIPs) with desirable functions to satisfy the extensive demands of biomedical applications. Herein, the recent research progress made with respect to bio-inspired imprinting materials is discussed in this review. First, the underlying mechanism and basic components of a typical molecular imprinting procedure are briefly explored. Then, emphasis is put on the introduction of diverse MITs and novel bio-inspired imprinting materials. Following these two sections, practical applications of MIPs in the field of biomedical science are focused on. Last but not least, perspectives on the remaining challenges and future development of bio-inspired imprinting materials are presented.

Suction-Cup-Inspired Adhesive Micromotors for Drug Delivery.

Micromotors have opened novel avenues for drug delivery due to their capacity for self-propelling. Attempts in this field trend towards ameliorating their functions to promote their clinical applications. In this paper, an ingenious suction-cup-inspired micromotor is presented with adhesive properties for drug delivery in the stomach. The micromotors are fabricated by using hydrogel replicating the structure of suction-cup-like microparticles, which derive from self-assembly of colloidal crystals under rapid solvent extraction, followed by loading magnesium (Mg) in the bottom spherical surface. The Mg-loaded micromotors can realize spontaneous movement due to the continual generation of hydrogen bubbles in gastric juice. The combination of unique suction-cup-like structure with excellent motion performance makes the micromotor an ideal carrier for drug delivery as they can efficiently adhere to the tissue. Moreover, benefiting from the porous structure, the hydrogel micromotors exhibit a high volume-surface ratio, which enables efficient drug loading. It is demonstrated that the suction-cup-inspired micromotors can adhere efficiently to the ulcer-region in the stomach and release drugs due to their distinctive architecture and spontaneous motion, exhibiting desirable curative effect of gastric ulcer. Thus, the suction-cup-inspired micromotors with adhesive properties are expected to advance the development of micromotor in clinical applications.