Flexible liquid-diode microtubes from multimodal microfluidics.

Directional transport of liquids is of great importance in energy saving, chemical/biomedical engineering, and microfluidics applications. Despite considerable progress in engineering different open surfaces to achieve liquid manipulation, the realization of diode-like liquid transport in enclosed spaces is still challenging. Here, a flexible diode microtube is presented for directional liquid transport within confined spaces using pulsed microfluidics. The microtubes exhibit sophisticated microstructures on the inner wall, replicated from a precisely controlled flow configuration in the microfluidic channel. Under the effect of asymmetric pinning and unbalanced Laplace pressure, such microtubes enable directional liquid transport in closed channels. More importantly, by integrating in situ flow lithography with the microfluidic system, segmented liquid diodes are fabricated as assembly units for the construction of fluidic-electronic circuits that perform logic operations. These results demonstrate the capacity of the present liquid-diode microtubes for flexible, directional, and programmable liquid transport. We believe that it can open an avenue for designing advanced fluidic circuit-based devices toward versatile practical applications.

Bioinspired nanogels as cell-free DNA trapping and scavenging organelles for rheumatoid arthritis treatment.

Excessive cell-free DNA (cfDNA) in the serum and synovium is considered a causative factor of rheumatoid arthritis (RA). Thus, cfDNA scavenging by using cationic polymers has been an effective therapeutic avenue, while these stratagems still suffer from systemic toxicity and unstable capture of cfDNA. Here, inspired by the biological charge-trapping effects and active degradation function of enzyme-containing organelles in vivo, we proposed a cationic peptide dendrimer nanogel with deoxyribonuclease I (DNase I) conjugation for the treatment of RA. Benefitting from their naturally derived peptide components, the resultant nanogels were highly biocompatible. More attractively, by tailoring them with a larger size and higher surface charge density, these cationic nanogels could achieve the fastest targeting capability, highest accumulation amounts, longer persistence time, and superior DNA scavenging capacity in inflamed joints. Based on these features, we have demonstrated that the organelle mimicking cationic nanogels could significantly down-regulate toll-like receptor (TLR)-9 signaling pathways and attenuate RA symptoms in collagen-induced arthritis mice. These results make the bioinspired DNase I conjugated cationic nanogels an ideal candidate for treating RA and other immune dysregulation diseases.

Cholesteric cellulose liquid crystal ink for three-dimensional structural coloration.

SignificanceWe propose a printable structural color ink composed of cholesteric cellulose liquid crystals together with gelatin and a thermal-responsive hydrogel. The ink is endowed with vivid structural colors and printability due to its constituents. Based on this, we print a series of graphics and three-dimensional (3D) objects with vivid color appearances. Moreover, the printed objects possess dual thermal responsiveness, which results in visible color change around body temperature. These performances, together with the biocompatibility of the constituents, indicate that the present ink represents a leap forward to the next-generation 3D printing and would unlock a wide range of real-life applications.

Photothermal Fish Gelatin-Graphene Microneedle Patches for Chronic Wound Treatment.

Microneedles are demonstrated as an effective strategy for chronic wound treatment. Great endeavors are devoted to developing microneedles with natural compositions and potent functions to promote therapeutic effects for wound healing. Herein, a novel graphene oxide-integrated methacrylated fish gelatin (GO-FGelMA) microneedle patch encapsulated with bacitracin and vascular endothelial growth factor (VEGF) is developed for chronic wound management. As the natural components and porous structures of FGelMA, the fabricated microneedle patches display satisfactory biocompatibility and drug-loading ability. Owing to the integration of graphene oxide, the microneedle patches can realize promoted drug release via near-infrared (NIR) irradiation. Besides, the encapsulated bacitracin and VEGF endow the microneedle patches with the ability to inhibit bacterial growth and promote angiogenesis. It is demonstrated that the GO-FGelMA microneedle patches with efficient drug release exert a positive influence on the wound healing process through reduced inflammation, enhanced wound closure, and improved tissue regeneration. Thus, it is believed that the proposed drugs-loaded GO-FGelMA microneedle patches will hold great potential in future chronic wound treatment.

Plant-Derived Chinese Herbal Hydrogel Microneedle Patches for Wound Healing.

Several natural Chinese herbal medicines have demonstrated considerable potential in facilitating wound healing, while the primary concern remains centered around optimizing formulation and structure to maximize their efficacy. To address this, a natural microneedles drug delivery system is proposed that harnesses gelatinized starch and key Chinese herbal ingredients-aloe vera and berberine. After gelatinized and aged in a well-designed mold, the starch-based microneedles are fabricated with suitable mechanical strength to load components. The resulting Chinese herbal hydrogel microneedles, enriched with integrated berberine and aloe, exhibit antibacterial, anti-inflammatory, and fibroblast growth-promoting properties, thereby facilitating wound healing in the whole process. In vivo experimental results underscore the notable achievements of the microneedles in early-stage antibacterial effects and subsequent tissue reconstruction, contributing significantly to the overall wound healing process. These results emphasize the advantageous combination of traditional Chinese medicine with microneedles, presenting a novel strategy for wound repair and opening new avenues for the application of traditional Chinese medicine.

Stem cell recruitment polypeptide hydrogel microcarriers with exosome delivery for osteoarthritis treatment.

With the accelerated aging tendency, osteoarthritis (OA) has become an intractable global public health challenge. Stem cells and their derivative exosome (Exo) have shown great potential in OA treatment. Research in this area tends to develop functional microcarriers for stem cell and Exo delivery to improve the therapeutic effect. Herein, we develop a novel system of Exo-encapsulated stem cell-recruitment hydrogel microcarriers from liquid nitrogen-assisted microfluidic electrospray for OA treatment. Benefited from the advanced droplet generation capability of microfluidics and mild cryogelation procedure, the resultant particles show uniform size dispersion and excellent biocompatibility. Moreover, acryloylated stem cell recruitment peptides SKPPGTSS are directly crosslinked within the particles by ultraviolet irradiation, thus simplifying the peptide coupling process and preventing its premature release. The SKPPGTSS-modified particles can recruit endogenous stem cells to promote cartilage repair and the released Exo from the particles further enhances the cartilage repair performance through synergistic effects. These features suggest that the proposed hydrogel microcarrier delivery system is a promising candidate for OA treatment.

Bio-inspired biorthogonal compartmental microparticles for tumor chemotherapy and photothermal therapy.

Microcarrier is a promising drug delivery system demonstrating significant value in treating cancers. One of the main goals is to devise microcarriers with ingenious structures and functions to achieve better therapeutic efficacy in tumors. Here, inspired by the nucleus-cytoplasm structure of cells and the material exchange reaction between them, we develop a type of biorthogonal compartmental microparticles (BCMs) from microfluidics that can separately load and sequentially release cyclooctene-modified doxorubicin prodrug (TCO-DOX) and tetrazine-modified indocyanine green (Tz-ICG) for tumor therapy. The Tz-ICG works not only as an activator for TCO-DOX but also as a photothermal agent, allowing for the combination of bioorthogonal chemotherapy and photothermal therapy (PTT). Besides, the modification of DOX with cyclooctene significantly decreases the systemic toxicity of DOX. As a result, the developed BCMs demonstrate efficient in vitro tumor cell eradication and exhibit notable tumor growth inhibition with favorable safety. These findings illustrate that the formulated BCMs establish a platform for bioorthogonal prodrug activation and localized delivery, holding significant potential for cancer therapy and related applications.

Roe-inspired stem cell microcapsules for inflammatory bowel disease treatment.

Mesenchymal stem cells (MSCs), which exert regulatory effects on various immune cells, have been a promising therapy for inflammatory bowel disease treatment. However, their therapeutic effects are limited by lack of nutritional supply, immune system attack, and low accumulation on the target site. Here, inspired by the natural incubation mechanism of roe, we present immune-isolating, wet-adhesive, and nutrient-rich microcapsules for therapeutic MSCs encapsulation. The adhesive shells were fabricated by ionic cross-linking of alginate and visible curing of epsilon-poly-L-lysine-graft-methacrylamide and dopamine methacrylamide, which encapsulated the liquid core of the MSCs and roe proteins. Due to the core-shell construction of the resultant microcapsules, the MSCs might escape from attack of the immune system while still maintaining immunomodulating functions. In addition, the roe proteins encapsulated in the core phase offered sufficient nutrient supply for MSCs' survival and proliferation. Furthermore, after intraperitoneal transplantation, the wet-adhesive radicals on the shell surface could immobilize the MSCs-encapsulating microcapsules onto the bowel. Based on these features, practical values of the roe-inspired microcapsules with MSCs encapsulation were demonstrated by applying them to treat dextran sulfate sodium (DSS)-induced colitis through increasing residence time, regulating immune imbalance, and relieving disease progression. We believe that the proposed roe-inspired microcapsules with MSCs encapsulation are potential for clinical application.

Spatiotemporal Catalytic Nanozymes Microneedle Patches with Opposite Properties for Wound Management.

Reactive oxygen species (ROS)-mediated biological catalysis involves serial programmed enzymatic reactions and plays an important part against infectious diseases; while the spatiotemporal control of catalytic treatment to break the limitations of the disease microenvironment is challenging. Here, a novel spatiotemporal catalytic microneedles patch (CMSP-MNs) integrated with dual-effective Cu2 MoS4 (CMS) and polydopamine (PDA) nanoparticles (NPs) for breaking microenvironment restrictions to treat wound infections is designed. Since CMS NPs are loaded in the needles, CMSP-MNs can catalytically generate diverse ROS to cause effective bacterial inactivation during bacterial infection process. Besides, PDA NPs are encapsulated in the backing layer, which facilitate ROS elimination and oxygen production for solving hypoxic problems in wound microenvironment and alleviating the expression of inflammatory factors during the inflammation process. Based on these features, it is demonstrated through cell and animal experiments that these nanozymes-integrated MNs patches can realize selective regulation of ROS level with bacterial inactivation and inflammatory treatment, resulting in minimized side effects of over-production ROS and effective anti-infected treatment. It is believed that the presented MNs can provide a new therapeutic strategy with spatiotemporal adjustable catalytic properties in biomedical areas.

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.

Cuttlefish-Inspired Photo-Responsive Antibacterial Microparticles with Natural Melanin Nanoparticles Spray.

Topical antibiotics can be utilized to treat periodontitis, while their delivery stratagems with controlled release and long-lasting bactericidal inhibition are yet challenging. Herein, inspired by the defensive behavior of cuttlefish expelling ink, this work develops innovative thermal-responsive melanin-integrated porous microparticles (MPs) through microfluidic synthesis for periodontitis treatment. These MPs are composed of melanin nanoparticles (NPs), poly(N-isopropylacrylamide) (PNIPAM), and agarose. Benefiting from the excellent biocompatibility and large surface area ratio of MPs, they can deliver abundant melanin NPs. Under near-infrared irradiation, the melanin NPs can convert photo energy into thermal energy. This leads to agarose melting and subsequent shrinkage of the microspheres induced by pNIPAM, thereby facilitating the release of melanin NPs. In addition, the released melanin NPs can serve as a highly effective photothermal agent, displaying potent antibacterial activity against porphyromonas gingivalis and possessing natural anti-inflammatory properties. These unique characteristics are further demonstrated through in vivo experiments, showing the antibacterial effects in the treatment of infected wounds and periodontitis. Therefore, the catfish-inspired photo-responsive antibacterial MPs with controlled-release drug delivery hold tremendous potential in clinical antibacterial applications.

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.

Multiple Bio-Actives Loaded Gellan Gum Microfibers from Microfluidics for Wound Healing.

Wound healing, known as a fundamental healthcare issue worldwide, has been attracting great attention from researchers. Here, novel bioactive gellan gum microfibers loaded with antibacterial peptides (ABPs) and vascular endothelial growth factor (VEGF) are proposed for wound healing by using microfluidic spinning. Benefitting from the high controllability of microfluidics, bioactive microfibers with uniform morphologies are obtained. The loaded ABPs are demonstrated to effectively act on bacteria at the wound site, reducing the risk of bacterial infection. Besides, sustained release of VEGF from microfibers helps to accelerate angiogenesis and further promote wound healing. The practical value of woven bioactive microfibers is demonstrated via animal experiments, where the wound healing process is greatly facilitated because of the excellent circulation of air and nutritious substances. Featured with the above properties, it is believed that the novel bioactive gellan gum microfibers would have a remarkable effect in the field of biomedical application, especially in promoting wound healing.

Adhesive Composite Microspheres with Dual Antibacterial Strategies for Infected Wound Healing.

Skin damage and infection pose a severe challenge to human health. Construction of a novel versatile dressing with good anti-infection and healing-promoting abilities is greatly expected. In this paper, nature-source-based composite microspheres with dual antibacterial mechanisms and bioadhesive features by microfluidics electrospray for infected wound healing is developed. The microspheres enable sustained release of copper ions, which not only show long-term antibacterial properties, but also play important role in wound-healing-related angiogenesis. Additionally, the microspheres are coated with polydopamine via self-polymerization, which renders the microspheres adhesive to the wound surface, and further enhance the antibacterial ability through photothermal energy conversion. Based on the dual antibacterial strategies provided by copper ions and polydopamine as well as the bioadhesive property, the composite microspheres exhibit excellent anti-infection and wound healing performances in a rat wound model. These results, along with the nature-source-based composition and biocompatibility, indicate the great potential of the microspheres in clinical wound repair.

Microfluidics for Drug Development: From Synthesis to Evaluation.

Drug development is a long process whose main content includes drug synthesis, drug delivery, and drug evaluation. Compared with conventional drug development procedures, microfluidics has emerged as a revolutionary technology in that it offers a miniaturized and highly controllable environment for bio(chemical) reactions to take place. It is also compatible with analytical strategies to implement integrated and high-throughput screening and evaluations. In this review, we provide a comprehensive summary of the entire microfluidics-based drug development system, from drug synthesis to drug evaluation. The challenges in the current status and the prospects for future development are also discussed. We believe that this review will promote communications throughout diversified scientific and engineering communities that will continue contributing to this burgeoning field.

Yunnan Baiyao-loaded multifunctional microneedle patches for rapid hemostasis and cutaneous wound healing.

Microneedle patches have been extensively employed for wound healing, while the lack of rapid hemostasis efficiency and multiple tissue-repair properties restrict their values in hemorrhagic wound applications. Herein, we propose a Yunnan Baiyao-loaded multifunctional microneedle patch, namely (BY + EGF)@MN, with deep tissue penetration, hemostasis efficiency and regenerative properties for hemorrhagic wound healing. The (BY + EGF)@MNs are designed with a BY-loaded Bletilla striata polysaccharide (BSP) base for rapid hemostasis and epidermal growth factor (EGF)-loaded GelMA tips for subsequent wound healing. As the BSP base can be fastly dissolved and completely release BY in 6 min to promote platelet adhesion and activate coagulation system, while the EGF can achieve a controlled and sustained release behavior in 7 days with the gradual degradation of the GelMA tips, the (BY + EGF)@MNs exhibit strong pro-coagulability and satisfactory hemostatic effect in a rat hepatic hemorrhage wound model. Based on the multifunctional characteristics, we have verified that when applied in rat cutaneous wounds, the proposed MNs can accelerate the wound healing process by enhancing neovascularization, fibroblast density, and collagen deposition. Thus, we believe that such (BY + EGF)@MNs are promising candidates for rapid hemostasis and diverse wound healing applications.

Bioinspired conductive cellulose liquid-crystal hydrogels as multifunctional electrical skins.

Bionic electronic skin (E-skin) that could convert external physical or mechanical stimuli into output signals has a wide range of applications including wearable devices, artificial prostheses, software robots, etc. Here, we present a chameleon-inspired multifunctional E-skin based on hydroxypropyl cellulose (HPC), Poly(Acrylamide-co-Acrylic acid) (PACA), and carbon nanotubes (CNTs) composited liquid-crystal hydrogel. We found that the HPC could still form cholesteric liquid-crystal photonic structures with the CNTs additive for enhancing their color saturation and PACA polymerization for locating their assembled periodic structures. As the composite hydrogel containing HPC elements and the PACA scaffold responds to different stimuli, such as temperature variations, mechanical pressure, and tension, it could correspondingly change its volume or internal nanostructure and report these as visible color switches. In addition, due to the additive of CNTs, the composite hydrogel could also output these stimuli as electrical resistance signals. Thus, the hydrogel E-skins had the ability of quantitatively feeding back external stimuli through electrical resistance as well as visually mapping the stimulating sites by color variation. This dual-signal sensing provides the ability of visible-user interaction as well as antiinterference, endowing the multifunctional E-skin with great application prospects.

Bioinspired programmable wettability arrays for droplets manipulation.

The manipulation of liquid droplets demonstrates great importance in various areas from laboratory research to our daily life. Here, inspired by the unique microstructure of plant stomata, we present a surface with programmable wettability arrays for droplets manipulation. The substrate film of this surface is constructed by using a coaxial capillary microfluidics to emulsify and pack graphene oxide (GO) hybrid N-isopropylacrylamide (NIPAM) hydrogel solution into silica nanoparticles-dispersed ethoxylated trimethylolpropane triacrylate (ETPTA) phase. Because of the distribution of the silica nanoparticles on the ETPTA interface, the outer surface of the film could achieve favorable hydrophobic property under selective fluorosilane decoration. Owing to the outstanding photothermal energy transformation property of the GO, the encapsulated hydrophilic hydrogel arrays could shrink back into the holes to expose their hydrophobic surface with near-infrared (NIR) irradiation; this imparts the composite film with remotely switchable surface droplet adhesion status. Based on this phenomenon, we have demonstrated controllable droplet sliding on programmable wettability pathways, together with effective droplet transfer for printing with mask integration, which remains difficult to realize by existing techniques.

Bioinspired MXene-integrated colloidal crystal arrays for multichannel bioinformation coding.

Information coding strategies are becoming increasingly crucial due to the storage demand brought by the information explosion. In particular, bioinformation coding has attracted great attention for its advantages of excellent storage capacity and long lifetime. Herein, we present an innovative bioinspired MXene-integrated photonic crystal (PhC) array for multichannel bioinformation coding. PhC arrays with similar structure to Stenocara beetle's back are utilized as the substrate, exhibiting properties of high throughput and stability. MXene nanosheets are further integrated on the PhC array's substrate with the assistance of the adhesion capacity of mussel-inspired dopamine (DA). Benefitting from their fluorescence resonance energy transfer effect, MXene nanosheets can quench the fluorescence signals of quantum dot (QD) modified DNA probes unless the corresponding targets exist. Additionally, these black MXene nanosheets can enhance the contrast of structural color. In this case, the encrypted information can be easily read out by simply observing the fluorescence signal of DNA probes. It is demonstrated that this strategy based on bioinspired MXene-integrated PhC arrays can realize high-throughput information encoding and encryption, which opens a chapter of bioinformation coding.

Spatial confinement toward creating artificial living systems.

Lifeforms are regulated by many physicochemical factors, and these factors could be controlled to play a role in the construction of artificial living systems. Among these factors, spatial confinement is an important one, which mediates biological behaviors at multiscale levels and participates in the biomanufacturing processes accordingly. This review describes how spatial confinement, as a fundamental biological phenomenon, provides cues for the construction of artificial living systems. Current knowledge about the role of spatial confinement in mediating individual cell behavior, collective cellular behavior, and tissue-level behavior are categorized. Endeavors on the synthesis of biomacromolecules, artificial cells, engineered tissues, and organoids in spatially confined bioreactors are then emphasized. After that, we discuss the cutting-edge applications of spatially confined artificial living systems in biomedical fields. Finally, we conclude by assessing the remaining challenges and future trends in the context of fundamental science, technical improvement, and practical applications.