Evidence for developmental vascular-associated necroptosis and its contribution to venous-lymphatic endothelial differentiation.

During development, apoptosis removes redundant cells and ensures proper organ morphogenesis. Necrosis is long known as an adult-bound inflammatory and pathologic cell death. Whether there exists physiological necrosis during early development has been speculated but yet clearly demonstrated. Here, we report evidence of necroptosis, a type of programmed necrosis, specifically in perivascular cells of cerebral cortex and skin at the early stage of development. Phosphorylated Mixed Lineage Kinase Domain-Like protein (MLKL), a key molecule in executing necroptosis, co-expressed with blood endothelial marker CD31 and venous-lymphatic progenitor marker Sox18. Depletion of Mlkl did not affect the formation of blood vessel network but increased the differentiation of venous-lymphatic lineage cells in postnatal cerebral cortex and skin. Consistently, significant enhancement of cerebrospinal fluid diffusion and lymphatic drainage was found in brain and skin of Mlkl-deficient mice. Under hypobaric hypoxia induced cerebral edema and inflammation induced skin edema, Mlkl mutation significantly attenuated brain-blood-barrier damage and edema formation. Our data, for the first time, demonstrated the presence of physiological vascular-associated necroptosis and its potential involvement in the development of venous-lymphatic vessels.

Multi-strand Fibers with Hierarchical Helical Structures Driven by Water or Moisture for Soft Actuators.

Smart actuators that combine excellent mechanical properties and responsive actuating performance like biological muscles have attracted considerable attention. In this study, a water/humidity responsive actuator, consisting of multi-strand carboxyl methyl cellulose (CMC) fibers with helical structures, was prepared using wet-spinning and twisting methods. The results showed that owing to the multi-strand structure, the actuator consisted of one-, two-, three-, and four-strand helical fibers, thus achieving a combination of high strength (∼27 MPa), high toughness (>10.34 MJ/m3), and large load limit (>0.30 N), which enable the actuator to theoretically withstand a weight that is at least 20,000 times its weight. Meanwhile, owing to the excellent moisture-responsive ability of CMC, the actuator, with a 5 g load, could achieve untwisting motion. Additionally, its maximum speed was approximately 2158 ± 233 rpm/m under water stimulation, whereas the recovery speed could reach 804 ± 44 rpm/m. Moreover, this untwisting-recovery reversible process was cyclic, whereas the shape and the actuating speed of the actuator remained stable after more than 150 cycles. The actuator improved the load limit that the fiber could withstand when driving under stimulation, thereby enabling the actuator to lift or move heavy objects like human muscles when executing spontaneously under external stimuli. This result shows considerable potential applications in artificial muscles and biomimetic robots.

Transient neurogenesis in ischemic cortex from Sox2+ astrocytes.

The adult cortex has long been regarded as non-neurogenic. Whether injury can induce neurogenesis in the adult cortex is still controversial. Here, we report that focal ischemia stimulates a transient wave of local neurogenesis. Using 5'-bromo-2'-deoxyuridine labeling, we demonstrated a rapid generation of doublecortin-positive neuroblasts that died quickly in mouse cerebral cortex following ischemia. Nestin-CreER-based cell ablation and fate mapping showed a small contribution of neuroblasts by subventricular zone neural stem cells. Using a mini-photothrombotic ischemia mouse model and retrovirus expressing green fluorescent protein labeling, we observed maturation of locally generated new neurons. Furthermore, fate tracing analyses using PDGFRα-, GFAP-, and Sox2-CreER mice showed a transient wave of neuroblast generation in mild ischemic cortex and identified that Sox2-positive astrocytes were the major neurogenic cells in adult cortex. In addition, a similar upregulation of Sox2 and appearance of neuroblasts were observed in the focal ischemic cortex of Macaca mulatta. Our findings demonstrated a transient neurogenic response of Sox2-positive astrocytes in ischemic cortex, which suggests the possibility of inducing neuronal regeneration by amplifying this intrinsic response in the future.

IRES-mediated Wnt2 translation in apoptotic neurons triggers astrocyte dedifferentiation.

Reactive astrogliosis usually bears some properties of neural progenitors. How injury triggers astrocyte dedifferentiation remains largely unclear. Here, we report that ischemia induces rapid up-regulation of Wnt2 protein in apoptotic neurons and activation of canonical Wnt signaling in reactive astrocytes in mice, primates and human. Local delivery of Wnt2 shRNA abolished the dedifferentiation of astrocytes while over-expressing Wnt2 promoted progenitor marker expression and neurogenesis. Both the activation of Wnt signaling and dedifferentiation of astrocytes was compromised in ischemic caspase-3-/- cortex. Over-expressing stabilized ß-catenin not only facilitated neurogenesis but also promoted functional recovery in ischemic caspase-3-/- mice. Further analysis showed that apoptotic neurons up-regulated Wnt2 protein via internal ribosome entry site (IRES)-mediated translation. Knocking down death associated protein 5 (DAP5), a key protein in IRES-mediated protein translation, significantly diminished Wnt activation and astrocyte dedifferentiation. Our data demonstrated an apoptosis-initiated Wnt-activating mechanism which triggers astrocytic dedifferentiation and facilitates neuronal regeneration.

Sweat-Resistant Silk Fibroin-Based Double Network Hydrogel Adhesives.

The adhesion between flexible epidermal sensors and human skin is essential for maintaining the stable functionality of the sensors. However, it is still challenging for epidermal electronic devices to achieve durable adhesion to the surface of the skin, especially under sweaty or humid conditions. Here, we report a silk fibroin-polyacrylamide (SF-PAAm) double network (DN) hydrogel adhesive with excellent biocompatibility, strong and durable adhesion on wet surfaces, and tunable adhesive properties. The hydrophilic PAAm network greatly improves the water retention capability of the DN hydrogel and reduces the ß-sheet crystalline content of SF, leading to excellent adhesive properties of the hydrogel across a wide range of humidity. The SF-PAAm DN hydrogel adhesive can be readily integrated with different epidermal sensor arrays and performs very well in real-time on-body sweat sensing. The SF-PAAm DN hydrogels have great potential for application in various epidermal healthcare sensors as well as medical adhesives for other medical applications.

Highly Stretchable Flame-Retardant Skin for Soft Robotics with Hydrogel-Montmorillonite-Based Translucent Matrix.

Flame-retardant coatings are crucial for intelligent systems operating in high-temperature (300-800°C) scenarios, which typically involve multi-joint discrete or continuous kinematic systems. These multi-segment motion generation systems call for conformable yet resilient skin for dexterous work, including firefighting, packaging inflammable substances, encapsulating energy storage devices, and preventing from burning. In fire scenes, a flame-retardant soft robot shall protect integrated electronic components safely and work for navigation and surveillance effectively. Here, we establish fire-resistant robotic mechanisms with montmorillonite (MMT)-biocompatible hydrogel skin, offering effective flame retardancy (∼78°C surface temperature after 3 min in fire) and high post-fire stretchability (∼360% uniaxial tensile strain). Fatigue test results in the MMT-hydrogel polymer matrix to portray a change in post-fire energy consumption of ∼21% (between the first cycle and the 200th cycle), further indicating robustness. MMT-hydrogel synthetic skin medium is then applied to everyday household items and electronics, offering appealing protections in fire scenes (≤10% capacitance loss after 3 min and ≤14% diode light-intensity loss after 1 min in fire). We deploy shape memory alloy (SMA) actuated inchworm-, starfish-, and snail-like locomotion (average velocity ∼12 mm·min-1) for translating inside fire applications. With the stretchable and flame-retardant translucent barriers, the MMT-hydrogel skinned soft robots demonstrate stable compression/relaxation cycles (25 cycles) within flames (4 min 10 s) while protecting the electronic components inside in fire scene. We solve the agility vs. endurance conundrum in this article with SMA actuation independently via Joule heating without a cross-talk from the surrounding high-temperature arena.

Super-Hydrophilic Zwitterionic Polymer Surface Modification Facilitates Liquid Transportation of Microfluidic Sweat Sensors.

The transportation of sweat in an epidermal sweat sensor is critical for the monitoring of biochemical compositions of human sweat. However, it is still a challenge to engineer microfluidic devices with super-wetting channels for such epidermal sweat sensors. Herein, a zwitterionic poly (2-methacryloyloxyethyl phosphorylcholine) (PMPC) modified microfluidic device with super-wetting and good liquid transport ability via an azo coupling reaction of PMPC onto the surface of polydimethylsiloxane microfluidic devices is reported. The obtained PMPC-modified microfluidic device can be integrated with flexible electrochemical sensor to measure the ion compositions of human sweat in real-time. The super-hydrophilic zwitterionic polymer surface modification can greatly facilitate the transportation of body fluids in microfluidic sensors for the detection of various biomarkers. Such microfluidic sensors have great potential for next-generation personalized healthcare.

Smart Actuators Based on External Stimulus Response.

Smart actuators refer to integrated devices that are composed of smart and artificial materials, and can provide actuation and dampening capabilities in response to single/multi external stimuli (such as light, heat, magnetism, electricity, humidity, and chemical reactions). Due to their capability of dynamically sensing and interaction with complex surroundings, smart actuators have attracted increasing attention in different application fields, such as artificial muscles, smart textiles, smart sensors, and soft robots. Among these intelligent material, functional hydrogels with fiber structure are of great value in the manufacture of smart actuators. In this review, we summarized the recent advances in stimuli-responsive actuators based on functional materials. We emphasized the important role of functional nano-material-based additives in the preparation of the stimulus response materials, then analyzed the driving response medium, the preparation method, and the performance of different stimuli responses in detail. In addition, some challenges and future prospects of smart actuators are reported.

Zwitterionic Polymer-Grafted Superhydrophilic and Superoleophobic Silk Fabrics for Anti-Oil Applications.

A highly anti-oil fabric membrane is synthesized by surface grafting of zwitterionic poly(sulfobetaine methacrylate) (PSBMA) onto the fabric surface. The fabric membrane is first enzymatically modified to create more reactive amine groups on the surface. A surface-initiated atom transfer radical polymerization (SI-ATRP) reaction is then performed to modify the fabric membrane surface with a dense PSBMA brush layer. Surface characterization indicates that the brush-grafted fabric membrane exhibits increased surface roughness and improved superhydrophilicity. The PSBMA-modified silk fabrics show a very large contact angle for oil droplets in water, and have excellent oil resistance in air and in water-oil mixtures.

Mechanochemical engineering of 2D materials for multiscale biointerfaces.

Atomically thin nanomaterials represent a unique paradigm for interfacing with biological systems due to their mechanical flexibility, exceptional interfacial area, and ease of chemical functionalization. In particular, these two-dimensional (2D) materials are able to bend, curve, and fold in response to biologically-generated forces or other external stimuli. Such origami-like folding of 2D materials into wrinkled or crumpled topographies allows them to withstand large deformations by accordion-like unfolding, with implications for stretchable and shape-changing devices. Here, we review how mechanically manipulated 2D materials can interact with biological systems across a multitude of length scales. We focus on recent work where wrinkling, crumpling, or bending of 2D materials permits new chemical and material properties, with four case studies: (i) programming biomolecular reactivity and enhanced sensing, (ii) directed adhesion and encapsulation of bacteria or mammalian cells, (iii) stimuli-responsive actuators and soft robotics, and (iv) stretchable barrier technologies and wearable human-scale sensors. Finally, we consider future directions for manufacturing, materials and systems integration, as well as biocompatibility. Taken together, these 2D materials may enable new avenues for ultrasensitive molecular detection, biomaterial scaffolds, soft machines, and wearable technologies.

Graphene hybrid colloidal crystal arrays with photo-controllable structural colors.

An intelligent structural color hydrogel with photo-controllable capability was developed by adding graphene oxide (GO) into colloidal particle solutions. The high charge characteristic of GO could significantly enhance the electrostatic repulsion effect between adjacent particles and promote the ordered assembly of the colloidal particles. The resultant colloidal crystal arrays (CCAs) with a small amount of GO additive were imparted with vivid angle-dependent structural colors due to the enhanced photon absorption of the hybrid materials, whereas their structural colors became dull and angle-independent with a high GO concentration, which contributes to the isotropic short-range ordered CAA nanostructures. It was demonstrated that the GO hybrid structural color hydrogels with temperature-sensitive polymer components featured photo-responsive properties, which provided remotely controllable dynamic structural colors for different patterns. These features of the GO hybrid structural color hydrogels make them promising for the applications of anti-counterfeiting barcode and other related fields.

Graphene Oxide-Enabled Synthesis of Metal Oxide Origamis for Soft Robotics.

Origami structures have been widely applied in various technologies especially in the fields of soft robotics. Metal oxides (MOs) have recently emerged as unconventional backbone materials for constructing complex origamis with distinct functionalities. However, the MO origami structures reported in the literature were rigid and not deformable, thus limiting their applications to soft robotics. Herein, we reported a graphene oxide (GO)-enabled templating synthesis to produce complex MO origami structures from their paper origami templates with high structural replication. The MO origami structures were next stabilized with elastomer, and the MO-elastomer origamis were able to be adapted into multiple actuation systems (including magnetic fields, shape-memory alloys, and pneumatics) for the fabrication of MO origami robots. Compared with conventional paper origami robots, the MO robots were lightweight, mechanically compliant, fire-retardant, magnetic responsive, and power efficient. We further demonstrated the legendary phoenix-fire-reborn concept in the soft robotics fields: a paper origami robot sacrificed itself in a fire scene and transformed itself into a downsized Al2O3 robot; the Al2O3 robot was able to crawl through a narrow tunnel where the original paper robot was unfit. These MO reconfigurable origamis provide an expanded material library for building soft robotics, and the functionalities of MO robots can be systematically engineered via the intercalation of various metal ions during the GO-enabled synthesis.

Cardiomyocyte-Driven Structural Color Actuation in Anisotropic Inverse Opals.

Biohybrid actuators composed of living tissues and artificial materials have attracted increasing interest in recent years because of their extraordinary function of dynamically sensing and interacting with complex bioelectrical signals. Here, a compound biohybrid actuator with self-driven actuation and self-reported feedback is designed based on an anisotropic inverse opal substrate with periodical elliptical macropores and a hydrogel filling. The benefit of the anisotropic surface topography and high biocompatibility of the hydrogel is that the planted cardiomyocytes could be induced into a highly ordered alignment with recovering autonomic beating ability on the elastic substrate. Because of the cell elongation and contraction during cardiomyocyte beating, the anisotropic inverse opal substrates undergo a synchronous cycle of deformation actuations, which can be reported as corresponding shifts of their photonic band gaps and structural colors. These self-driven biohybrid actuators could be used as elements for the construction of a soft-bodied structural color robot, such as a biomimetic guppy with a swinging tail. Besides, with the integration of a self-driven biohybrid actuator and microfluidics, the advanced heart-on-a-chip system with the feature of microphysiological visuality has been developed for integrated cell monitoring and drug testing. This anisotropic inverse opal-derived biohybrid actuator could be widely applied in biomedical engineering.

Cardiomyocytes-Actuated Morpho Butterfly Wings.

Morpho butterflies are famous for their wings' brilliant structural colors arising from periodic nanostructures, which show great potential value for fundamental research and practical applications. Here, a novel cellular mechanical visualizable biosensor formed by assembling engineered cardiac tissues on the Morpho butterfly wings is presented. The assembled cardiomyocytes benefit from the periodic parallel nanoridges of the wings and can recover their autonomic beating ability with guided cellular orientation and good contraction performance. As the beating processes are accompanied by the cardiomyocytes' elongation and contraction, the elastic butterfly wing substrate undergoes the same cycle of deformations, which causes corresponding synchronous shifts in their structural colors and photonic bandgaps for self-reporting of the cell mechanics. It is demonstrated that this self-reporting performance can be further improved by adding oriented carbon nanotubes in the nanoridges of the wings for the culture. In addition, taking advantage of the similar size of the cardiomyocyte and a single Morpho wing scale, the investigation of single-cell-level mechanics can be realized by detecting the optical performance of a single scale. These remarkable properties make these butterfly wings ideal platforms for biomedical research.

64Cu-Labeled multifunctional dendrimers for targeted tumor PET imaging.

We report the use of multifunctional folic acid (FA)-modified dendrimers as a platform to radiolabel with 64Cu for PET imaging of folate receptor (FR)-expressing tumors. In this study, amine-terminated generation 5 (G5) poly(amidoamine) dendrimers were sequentially modified with fluorescein isothiocyanate (FI), FA, and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), followed by acetylation of the remaining dendrimer terminal amines. The as-formed multifunctional DOTA-FA-FI-G5·NHAc dendrimers were then radiolabeled with 64Cu via the DOTA chelation. We show that the FA modification renders the dendrimers with targeting specificity to cancer cells overexpressing FR in vitro. Importantly, the radiolabeled 64Cu-DOTA-FA-FI-G5·NHAc dendrimers can be used as a nanoprobe for specific targeting of FR-overexpressing cancer cells in vitro and targeted microPET imaging of the FR-expressing xenografted tumor model in vivo. The developed 64Cu-labeled multifunctional dendrimeric nanoprobe may hold great promise to be used for targeted PET imaging of different types of FR-expressing cancer.

Cuttlefish Ink Tagged Photonic Crystal Particles and Their Ion-Responsive Construction.

Colloidal crystal materials have potential values in coding, sensing, displaying and so on. Attempts to promote these values tend to focus on the development of functional colloidal crystal materials with high color saturations and bright structural colors for practical applications. Thus, this work presented novel cuttlefish ink nanoparticles doped colloidal crystal particle material, which had distinguishable and high saturation colors, and could response to the electric field and pH obviously. It was also found that the doping could result in a short-range order and long-range disorder structure of the colloidal crystals, which endowed them with wide viewing angles. More importantly, by using electric field and ions dual-responsive hydrogel to replicate the composite colloidal crystals particles, the resultant cuttlefish ink nanoparticles doped inverse opal particles were imparted with the same high saturation vivid structural colors, as well as obviously structural color tunability. These features make the cuttlefish ink nanoparticles doped colloidal crystal particles ideal for many practical applications where structural color materials is needed.

Bioinspired living structural color hydrogels.

Structural color materials from existing natural organisms have been widely studied to enable artificial manufacture. Variable iridescence has attracted particular interest because of the displays of various brilliant examples. Existing synthetic, variable, structural color materials require external stimuli to provide changing displays, despite autonomous regulation being widespread among natural organisms, and therefore suffer from inherent limitations. Inspired by the structural color regulation mechanism of chameleons, we present a conceptually different structural color material that has autonomic regulation capability by assembling engineered cardiomyocyte tissues on synthetic inverse opal hydrogel films. The cell elongation and contraction in the beating processes of the cardiomyocytes caused the inverse opal structure of the substrate film to follow the same cycle of volume or morphology changes. This was observed as the synchronous shifting of its photonic band gap and structural colors. Such biohybrid structural color hydrogels can be used to construct a variety of living materials, such as two-dimensional self-regulating structural color patterns and three-dimensional dynamic Morpho butterflies. These examples indicated that the stratagem could provide an intrinsic color-sensing feedback to modify the system behavior/action for future biohybrid robots. In addition, by integrating the biohybrid structural color hydrogels into microfluidics, we developed a "heart-on-a-chip" platform featuring microphysiological visuality for biological research and drug screening. This biohybrid, living, structural color hydrogel may be widely used in the design of a variety of intelligent actuators and soft robotic devices.

Antibacterial Structural Color Hydrogels.

Structural color hydrogels with lasting survivability are important for many applications, but they still lack anti-biodegradation capability. Thus, we herein present novel antibacterial structural color hydrogels by simply integrating silver nanoparticles (AgNPs) in situ into the hydrogel materials. Because the integrated AgNPs possessed wide and excellent antibacterial abilities, the structural color hydrogels could prevent bacterial adhesion, avoid hydrogel damage, and maintain their vivid structural colors during their application and storage. It was demonstrated that the AgNP-tagged poly(N-isopropylacrylamide) structural color hydrogels could retain their original thermal-responsive color transition even when the AgNP-free hydrogels were degraded by bacteria and that the AgNP-integrated self-healing structural color protein hydrogels could save their self-repairing property instead of being degraded by bacteria. These features indicated that the antibacterial structural color hydrogels could be amenable to a variety of practical biomedical applications.

Bioinspired Heterogeneous Structural Color Stripes from Capillaries.

As an important characteristic of many creatures, structural colors play a crucial role in the survival of organisms. Inspired by these features, an intelligent structural color material with a heterogeneous striped pattern and stimuli-responsivity by fast self-assembly of colloidal nanoparticles in capillaries with a certain diameter range are presented here. The width, spacing, color, and even combination of the structural color stripe patterns can be precisely tailored by adjusting the self-assembly parameters. Attractively, with the integration of a near-infrared (NIR) light responsive graphene hydrogel into the structural color stripe pattern, the materials are endowed with light-controlled reversible bending behavior with self-reporting color indication. It is demonstrated that the striped structural color materials can be used as NIR-light-triggered dynamic barcode labels for the anti-counterfeiting of different products. These features of the bioinspired structural color stripe pattern materials indicate their potential values for mimicking structural color organisms, which will find important applications in constructing intelligent sensors, anti-counterfeiting devices, and so on.

Responsive photonic barcodes for sensitive multiplex bioassay.

Barcodes have a demonstrated value for multiplex high-throughput bioassays. The tendency of this technology is to pursue high sensitivity target screening. Herein, we presented a new type of inverse opal-structured poly(N-isopropylacrylamide) (pNIPAM) hydrogel photonic crystal (PhC) barcodes with the function of fluorescent signal self-amplification for the detection. During the bio-reaction process at body temperature, the pNIPAM hydrogel barcodes kept swelling, and their inverse opal structure with interconnected pores provided unblocked channels for the targets to diffuse into the voids of the barcodes and react. During the detection process, the barcodes were kept at a volume phase transition temperature (VPTT) to shrink their volume; this resulted in an obvious increase in the density of fluorescent molecules and signal amplification. It was demonstrated that the responsive barcodes could achieve the limits of detection (LOD) of α-fetoprotein (AFP) and carcinoembryonic antigen (CEA) at 0.623 ng mL-1 and 0.492 ng mL-1, respectively. In addition, the proposed barcodes showed good multiplex detection capacity with acceptable cross-reactivity, accuracy, and reproducibility, and the results were consistent with those of common clinical laboratory methods for the detection of clinical samples. These features of the inverse opal-structured responsive hydrogel barcodes indicate that they are ideal technology for high-sensitive multiplex bioassays.