Micropillar with Radial Gradient Modulus Enables Robust Adhesion and Friction.

The gradient modulus in beetle setae plays a critical role in allowing it to stand and walk on natural surfaces. Mimicking beetle setae to create a modulus gradient in microscale, especially in the direction of setae radius, can achieve reliable contact and thus strong adhesion. However, it remains highly challenging to achieve modulus gradient along radial directions in setae-like structures. Here, polydimethylsiloxane (PDMS) micropillar with radial gradient modulus, (termed GM), is successfully constructed by making use of the polymerization inhibitor in the photosensitive resin template. GM gains adhesion up to 84 kPa, which is 2.3 and 4.7 times of soft homogeneous micropillars (SH) and hard homogeneous micropillars (HH), respectively. The radial gradient modulus facilitates contact formation on various surfaces and shifts stress concentration from contact perimeter to the center, resulting in adhesion enhancement. Meanwhile, GM achieves strong friction of 8.1 mN, which is 1.2 and 2.6 times of SH and HH, respectively. Moreover, GM possesses high robustness, maintaining strong adhesion and friction after 400 cycles of tests. The work here not only provides a robust structure for strong adhesion and friction, but also establishes a strategy to create modulus gradient at micron-scale.

Wires with Continuous Sabal Leaf-Patterned Micropores Constructed by Freeze Printing for a Wearable Sensor Responsible to Multiple Deformations.

The design of porous structure in wearable sensors is very important for the detection of mechanical signals. However, it remains challenging to construct a porous structure capable of detecting all kinds of mechanical signals. Here, round wire with long-range orientated micropores (RW-LOM) is fabricated by a newly established freeze printing technique and constructed into a wearable sensor by the incorporation of carbon nanotubes and polydimethylsiloxane. The Sabal leaf-like lamellar structure in RW-LOM is realized and can be tuned by the proper coordination of slurry concentration and the printing parameters. The fine structures in RW-LOM allow the wearable sensor to detect compression, stretching, twisting, and bending with a high sensitivity, stability, and broad detecting range. This work not only provides a wearable sensor with high stability and high sensitivity but also establishes a technique to construct porous wires that could find applications in the fields like intelligent industry and healthcare.

Improvement in Mechanical Properties of 3D-Printed PEEK Structure by Nonsolvent Vapor Annealing.

The broad applications of 3D-printed poly-ether-ether-ketone (3D-PEEK) structures are largely hampered by their inadequate mechanical properties that can be improved by post treatments. At present, thermal annealing is generally used to improve the mechanical properties of 3D-PEEK. However, it cannot simultaneously improve strength and ductility. Here, a cost-effective postprocessing method is developed to improve the mechanical properties of 3D-PEEK, based on annealing in nonsolvent vapor at room temperature. The annealing in nonsolvent vapor at room temperature simultaneously improves the strength, ductility, and fracture energy of as-printed 3D-PEEK by 22.6%, 151.3%, and 109.1%, respectively. The improved mechanical properties are attributed to enhanced interfacial bonding, increased crystallinity, decreased pinhole defects, and stress relaxation in the 3D-PEEK. Moreover, the annealing in both polar solvents (such as acetone and chloroform) and nonpolar solvents (such as n-hexane) are demonstrated to be effective for improving the mechanical properties of 3D-PEEK. The nonsolvent vapor-annealed 3D-PEEK can thus have potential applications in the fields of medical implants, automotive, aerospace, and more.

Hypoxic Preconditioning Enhances the Efficacy of Mesenchymal Stem Cells-Derived Conditioned Medium in Switching Microglia toward Anti-inflammatory Polarization in Ischemia/Reperfusion.

Activation of pro-inflammatory microglia is an important mechanism of the cerebral ischemia-reperfusion (I/R)-induced neuronal injury and dysfunction. Mesenchymal stem cells (MSCs) together with their paracrine factors demonstrated curative potential in immune disorders and inflammatory diseases, as well as in ischemic diseases. However, it remains unclear whether conditioned medium from MSCs could effectively regulate the activation and polarization of microglia exposed to I/R stimulation. In this study, we investigated the effects of conditioned medium from bone marrow MSCs (BMSCs-CM) on I/R-stimulated microglia and the potential mechanism involved, as well as the way to obtain more effective BMSCs-CM. First, cell model of oxygen-glucose deprivation/reoxygenation (OGD/R) was established in microglia to mimic the I/R. BMSCs-CM from different culture conditions (normoxic: 21% O2; hypoxic: 1% O2; hypoxia preconditioning: preconditioning with 1% O2 for 24 h) was used to treat the microglia. Our results showed that BMSCs-CM effectively promoted the survival and alleviated the injury of microglia. Moreover, in microglia exposed to OGD/R, BMSCs-CM inhibited significantly the expression of pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6), CD86 and inducible nitric oxide synthase, whereas upregulated the levels of anti-inflammatory cytokine (IL-10), CD206 and Arginase-1. These results suggested that BMSCs-CM promoted the polarization of anti-inflammatory microglia. In particular, BMSCs-CM from cultures with hypoxia preconditioning was more effective in alleviating cell injury and promoting anti-inflammatory microglia polarization than BMSCs-CM from normoxic cultures and from hypoxic cultures. Furthermore, inhibition of exosomes secretion could largely mitigate these effects of BMSCs-CM. In conclusion, our results suggested that hypoxia preconditioning of BMSCs could enhance the efficacy of BMSCs-CM in alleviating OGD/R-induced injury and in promoting the anti-inflammatory polarization of microglia, and these beneficial effects of BMSCs-CM owed substantially to exosomes.

Oral delivery of insulin with intelligent glucose-responsive switch for blood glucose regulation.

BACKGROUND: The traditional treatment for diabetes usually requires frequent insulin injections to maintain normoglycemia, which is painful and difficult to achieve blood glucose control. RESULTS: To solve these problems, a non-invasive and painless oral delivery nanoparticle system with bioadhesive ability was developed by amphipathic 2-nitroimidazole-L-cysteine-alginate (NI-CYS-ALG) conjugates. Moreover, in order to enhance blood glucose regulation, an intelligent glucose-responsive switch in this nanoparticle system was achieved by loading with insulin and glucose oxidase (GOx) which could supply a stimulus-sensitive turnover strategy. In vitro tests illustrated that the insulin release behavior was switched "ON" in response to hyperglycemic state by GOx catalysis and "OFF" by normal glucose levels. Moreover, in vivo tests on type I diabetic rats, this system displayed a significant hypoglycemic effect, avoiding hyperglycemia and maintaining a normal range for up to 14 h after oral administration. CONCLUSION: The stimulus-sensitive turnover strategy with bioadhesive oral delivery mode indicates a potential for the development of synthetic GR-NPs for diabetes therapy, which may provide a rational design of proteins, low molecular drugs, as well as nucleic acids, for intelligent releasing via the oral route.

Bone marrow mesenchymal stem cells-derived conditioned medium protects cardiomyocytes from hypoxia/reoxygenation-induced injury through Notch2/mTOR/autophagy signaling.

Bone marrow mesenchymal stem cells (BMSC) can ameliorate ischemic injury of various tissues. However, the molecular mechanisms involved remain to be clarified. In this study, we intend to investigate the effects of BMSC-derived conditioned medium (BMSC-CM) on hypoxia/reoxygenation (H/R)-induced injury of H9c2 myocardial cells, and the potential mechanisms. Cell injury was determined through level of cell viability, lactate dehydrogenase (LDH) release, total intracellular reactive oxygen species (ROS), mitochondrial membrane potential (Δψm), and cell apoptosis. Autophagic activity of cells was detected through levels of the autophagy-associated proteins and autophagic flux. Results showed that BMSC-CM alleviated H/R-induced injury in H9c2 cells, as demonstrated by increased cell viability and Δψm, decreased ROS production, LDH release, and cell apoptosis. Furthermore, the H/R treatment induced a decrease in autophagic activity and an increase in Notch2 signaling activation in H9c2 cells. In the presence of BMSC-CM, the autophagic activity impaired by the H/R treatment was upregulated with decreased phosphorylation of mTOR, and the activation of Notch2 signaling was downregulated. These effects of BMSC-CM could be replicated by Notch signaling inhibitor. In contrast, inhibitors of cell autophagy including chloroquine (CQ) and 3-methyladenine, diminished the protective effects of BMSC-CM. Taken together results, our study showed that BMSC-CM could protect H9c2 cells from H/R-induced injury potentially through regulating Notch2/mTOR/autophagy signaling. These findings may provide a novel insight into the mechanisms of BMSC-CM in therapy of myocardial ischemia/reperfusion injury as well as other ischemic diseases.

Continuous Gradient Nanoporous Film Enabled by Delayed Directional Diffusion of Solvent and Selective Swelling.

Nature-inspired porous structures are highly desired in the fields of new materials, sustainable energy, biological and chemical science, and so forth. Here, a new strategy for the fabrication of continuous, gradient nanoporous polystyrene- block-poly(2-vinylpyridine) (PS- b-P2VP) film is established. The continuous nanopore gradient along the direction of film thickness (∼120 µm) is achieved via delayed directional diffusion of dynamic binary solvent of ethanol/water and selective swelling of P2VP domains. Ethanol in binary solvent diffuses into the film from one side to another, which is retarded by the water gate as water is concentrated at the film surface. The delayed diffusion matches the swelling rate of P2VP domains, forming the continuous nanopore gradient normal to the film surface.

High drug-loading gold nanoclusters for responsive glucose control in type 1 diabetes.

BACKGROUND: Diabetes is one of the biggest medical challenges worldwide. The key to efficiently treat type 1 diabetes is to accurately inject insulin according to the blood glucose levels. In this study, we aimed to develop an intelligent insulin-releasing gold nanocluster system that responds to environmental glucose concentrations. RESULTS: We employed gold nanoclusters (AuNCs) as a novel carrier nanomaterial by taking advantage of their high drug-loading capacity. We prepared AuNCs in the protection of bovine serum albumin, and we decorated AuNCs with 3-aminophenylboronic acid (PBA) as a glucose-responsive factor. Then we grafted insulin onto the surface to obtain the glucose-responsive insulin-releasing system, AuNC-PBA-Ins complex. The AuNC-PBA-Ins complex exhibited high sensitivity to glucose concentration, and rapidly released insulin in high glucose concentration in vitro. In the type 1 diabetic mouse model in vivo, the AuNC-PBA-Ins complex effectively released insulin and regulated blood glucose level in the normoglycemic state for up to 3 days. CONCLUSIONS: We successfully developed a phenylboronic acid-functionalized gold nanocluster system (AuNC-PBA-Ins) for responsive insulin release and glucose regulation in type 1 diabetes. This nanocluster system mimics the function of blood glucose regulation of pancreas in the body and may have potential applications in the theranostics of diabetes.

Bioinspired super-hydrophilic zwitterionic polymer armor combats thrombosis and infection of vascular catheters.

Thrombosis and infection are two major complications associated with central venous catheters (CVCs), which significantly contribute to morbidity and mortality. Antifouling coating strategies currently represent an efficient approach for addressing such complications. However, existing antifouling coatings have limitations in terms of both duration and effectiveness. Herein, we propose a durable zwitterionic polymer armor for catheters. This armor is realized by pre-coating with a robust phenol-polyamine film inspired by insect sclerotization, followed by grafting of poly-2-methacryloyloxyethyl phosphorylcholine (pMPC) via in-situ radical polymerization. The resulting pMPC coating armor exhibits super-hydrophilicity, thereby forming a highly hydrated shell that effectively prevents bacterial adhesion and inhibits the adsorption and activation of fibrinogen and platelets in vitro. In practical applications, the armored catheters significantly reduced inflammation and prevented biofilm formation in a rat subcutaneous infection model, as well as inhibited thrombus formation in a rabbit jugular vein model. Overall, our robust zwitterionic polymer coating presents a promising solution for reducing infections and thrombosis associated with vascular catheters.

Pericytes, stem-cell-like cells, but not mesenchymal stem cells are recruited to support microvascular tube stabilization.

An experimental model is introduced for the induction of endothelial cell (EC) tubulogenesis after 24 h of incubation on micropatterned polymer surfaces. Pericytes or mesenchymal stem cells are added separately to this system to evaluate their effect on tubular stabilization. In the absence of additional cells, the tubular structures are lost after 36 h. Addition of only pericytes, however, stabilizes the EC vasculogenic tubes.

Modulation of lumen formation by microgeometrical bioactive cues and migration mode of actin machinery.

How endothelial cells (ECs) express the particular filopodial or lamellipodial form of the actin machinery is critical to understanding EC functions such as angiogenesis and sprouting. It is not known how these mechanisms coordinately promote lumen formation of ECs. Here, adhesion molecules (RGD peptides) and inductor molecules (BMP-2 mimetic peptides) are micropatterned onto polymer surfaces by a photolithographic technique to induce filopodial and lamellipodial migration modes. Firstly, the effects of peptide microgeometrical distribution on EC adhesion, orientation and morphogenesis are evaluated. Large micropatterns (100 µm) promote EC orientation without lumen formation, whereas small micropatterns (10-50 µm) elicit a collective cell organization and induce EC lumen formation, in the case of RGD peptides. Secondly, the correlation between EC actin machinery expression and EC self-assembly into lumen formation is addressed. Only the filopodial migration mode (mimicked by RGD) but not lamellipodial migration mode (mimicked by BMP-2) promotes EC lumen formation. This work gives a new concept for the design of biomaterials for tissue engineering and may provide new insight for angiogenesis inhibition on tumors.

Microneedle-based glucose monitoring: a review from sampling methods to wearable biosensors.

Blood glucose (BG) monitoring is critical for diabetes management. In recent years, microneedle (MN)-based technology has attracted emerging attention in glucose sensing and detection. In this review, we summarized MN-based sampling for glucose collection and glucose analysis in detail. First, different principles of MN-based biofluid extraction were elaborated, including external negative pressure, capillary force, swelling force and iontophoresis, which would guide the shape design and material optimization of MNs. Second, MNs coupled with different analysis approaches, including Raman methods, colorimetry, fluorescence, and electrochemical sensing, were emphasized to exhibit the trend towards highly integrated wearable sensors. Finally, the future development prospects of MN-based devices were discussed.

Intradermal delivery of an angiotensin II receptor blocker using a personalized microneedle patch for treatment of hypertrophic scars.

High-quality postoperative rehabilitation is the focus of most patients currently, and hypertrophic scar (HS) greatly reduces the patient's quality of life due to the symptom of severe itching. Traditional HS therapies are associated with limitations, such as poor drug delivery efficiency for topical administration and severe pain for intralesional injection. In this study, we developed a personalized microneedle patch system for minimally invasive and effective treatment of HSs. The microneedle patches were personalized designed and fabricated with 3D printing in order to adapt to individual HS. The optimized microneedle patches were composed of dissolving gelatin and starch and loaded with losartan. Losartan, as a drug class of angiotensin II receptor blockers (ARBs), can effectively inhibit the proliferation and migration of hypertrophic scar fibroblasts (HSFs) and downregulate the gene expression related to scar formation in HSFs. The dissolving microneedle patches exhibited strong mechanical strength, effectively penetrated the stratum corneum of HSs and increased the losartan delivery into HSs upon dissolution of gelatin and starch. Together, the losartan-loaded microneedle patches effectively inhibited the formation of HSs in rabbit ears with reduced scar elevation index (SEI), and decreased fibrosis and collagen deposition in HSs. This personalized microneedle patch system increases the drug delivery efficiency into HSs with minimal invasion, and opens a new window for personalized management and treatment of skin diseases.

Peptide immobilization on polyethylene terephthalate surfaces to study specific endothelial cell adhesion, spreading and migration.

To control specific endothelial cell (EC) functions, cell adhesive RGDS, EC specific REDV and YIGSR peptides, and angiogenic SVVYGLR sequences were covalently immobilized onto polyethylene terephthalate (PET) surfaces for the purpose of cell culture. X-ray photoelectron spectroscopy, atomic force microscopy, fluorescence microscopy and contact angle measurement were employed for characterization of surface modifications. The peptide density on PET surfaces was evaluated by fluorescence microscopy. The surfaces immobilized with peptides were exposed to human umbilical vein endothelial cells to study their specific effects onto EC functions. The results showed that the surface functionalized by these peptides enhanced the EC adhesion, spreading and migration as compared with native PET surfaces. Specifically, the RGDS peptides induced more cell adhesion than other peptides. The YIGSR and SVVYGLR sequences induced more cell spreading and cell migration, represented by intense focal adhesion at the leading edges of cell spreading and migration. The bi-functionalization of RGDS and SVVYGLR peptides (MIX) combined the advantages of both peptides and induced significant EC adhesion, spreading and migration. Our study indicates that the surface functionalization by peptides specific for ECs, especially the combination of RGDS with SVVYGLR or YIGSR peptides, has potential applications in promoting endothelialization of vascular prostheses and for construction of vascularized tissues in tissue engineering.

Fast Self-Assembly of Photonic Crystal Hydrogel for Wearable Strain and Temperature Sensor.

Structural colors from photonic crystals (PCs) have attracted emerging attention in the research area of wearable sensors. Conventional self-assembly of PC takes days to weeks. Here, a fast self-assembly method of PC with horizontal precipitation of silica nanoparticles (NPs) in a polydimethylsiloxane fence, which can be completed within 1-4 h depending on the fence parameters, is introduced. The resultant PC exhibits tunable structural colors in the entire visible spectrum. With infiltration of composite hydrogels containing acrylic acid, acrylamide, chitosan, and carbon nanotubes (CNTs) into the gaps of NPs to form an inverse opal PC, a structural color hydrogel that can quickly respond to different stimuli, including strain and temperature, is obtained. Moreover, with the addition of CNTs, the composite PC hydrogel can also output an electronic signal together with optical color changes. Based on these extraordinary responsive behaviors, the PC hydrogel sensor for quantitative feedback to external stimuli of stretching, bending, pressing, and thermal stimuli, with brilliant color change and electronic signal outputs simultaneously, is demonstrated. This fast-assembled PC hydrogel with excellent responsive properties has great potential for applications in wearable devices, mechanical sensors, temperature sensors, and colorimetric displays.

Responsive hydrogel-based microneedle dressing for diabetic wound healing.

Wound healing is a critical challenge in diabetic patients, mainly due to long-term dysglycemia and its related pathological complications. Subcutaneous insulin injection represents a typical clinical solution, while the low controllability of insulin administration commonly leads to a result far from the optimal therapeutic effect. In this work, we developed a glucose-responsive insulin-releasing hydrogel for microneedle dressing fabrication and then investigated its effects on diabetic wound healing. The hydrogel system was composed of biocompatible gelatin methacrylate (GelMa), glucose-responsive monomer 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AFPBA) and gluconic insulin (G-insulin), and the Gel-AFPBA-ins hydrogel-based microneedle dressing was developed by replicating PDMS molds. The resultant hydrogel microneedle dressing exhibited adequate mechanical properties, high biocompatibility, glucose-responsive insulin release behavior upon exposure to different glucose solutions, and potent adhesion to the skin compared to hydrogels without microstructures. The microneedle dressing could accelerate the diabetic wound healing process with decreased inflammatory reaction, enhanced collagen deposition on the regenerated tissue sites, and improved blood glucose control in animals. Therefore, the glucose-responsive insulin-releasing hydrogel microneedle dressing is effective in diabetic wound management and has potential for treatment of other chronic skin injuries.

Anisotropic Wettability of Bioinspired Surface Characterized by Friction Force.

Bioinspired surfaces with special wettabilities attract increasing attention due to their extensive applications in many fields. However, the characterizations of surface wettability by contact angle (CA) and sliding angle (SA) have clear drawbacks. Here, by using an array of triangular micropillars (ATM) prepared by soft lithography, the merits of measuring the friction force of a water droplet on ATM over measurements of CA and SA in characterizing the surface wettability are demonstrated. The CA and SA measurements show ignorable differences in the wettabilities of ATM in opposite directions (1.13%) and that with different periodic parameters under the elongation ranging from 0 to 70%. In contrast, the friction measurement reveals a difference of > 10% in opposite directions. Moreover, the friction force shows a strong dependence on the periodic parameters which is regulated by mechanical stretching. Increasing the elongation from 0 to 50% increases the static and kinetic friction force up to 23.0% and 22.9%, respectively. Moreover, the stick-slip pattern during kinetic friction can reveal the periodic features of the measured surface. The friction force measurement is a sensitive technique that could find applications in the characterization of surface wettabilities.

Adhesion behaviors of water droplets on bioinspired superhydrophobic surfaces.

The adhesion behaviors of droplets on surfaces are attracting increasing attention due to their various applications. Many bioinspired superhydrophobic surfaces with different adhesion states have been constructed in order to mimic the functions of natural surfaces such as a lotus leaf, a rose petal, butterfly wings, etc. In this review, we first present a brief introduction to the fundamental theories of the adhesion behaviors of droplets on various surfaces, including low adhesion, high adhesion and anisotropic adhesion states. Then, different techniques to characterize droplet adhesion on these surfaces, including the rotating disk technique, the atomic force microscope cantilever technique, and capillary sensor-based techniques, are described. Wetting behaviors, and the switching between different adhesion states on bioinspired surfaces, are also summarized and discussed. Subsequently, the diverse applications of bioinspired surfaces, including water collection, liquid transport, drag reduction, and oil/water separation, are discussed. Finally, the challenges of using liquid adhesion behaviors on various surfaces, and future applications of these surfaces, are discussed.

A two-stage amplified PZT sensor for monitoring lung and heart sounds in discharged pneumonia patients.

Assessment of lung and heart states is of critical importance for patients with pneumonia. In this study, we present a small-sized and ultrasensitive accelerometer for continuous monitoring of lung and heart sounds to evaluate the lung and heart states of patients. Based on two-stage amplification, which consists of an asymmetric gapped cantilever and a charge amplifier, our accelerometer exhibited an extremely high ratio of sensitivity to noise compared with conventional structures. Our sensor achieves a high sensitivity of 9.2 V/g at frequencies less than 1000 Hz, making it suitable to use to monitor weak physiological signals, including heart and lung sounds. For the first time, lung injury, heart injury, and both lung and heart injuries in discharged pneumonia patients were revealed by our sensor device. Our sound sensor also successfully tracked the recovery course of the discharged pneumonia patients. Over time, the lung and heart states of the patients gradually improved after discharge. Our observations were in good agreement with clinical reports. Compared with conventional medical instruments, our sensor device provides rapid and highly sensitive detection of lung and heart sounds, which greatly helps in the evaluation of lung and heart states of pneumonia patients. This sensor provides a cost-effective alternative approach to the diagnosis and prognosis of pneumonia and has the potential for clinical and home-use health monitoring.

Bionic microenvironment-inspired synergistic effect of anisotropic micro-nanocomposite topology and biology cues on peripheral nerve regeneration.

Anisotropic topographies and biological cues can simulate the regenerative microenvironment of nerve from physical and biological aspects, which show promising application in nerve regeneration. However, their synergetic influence on injured peripheral nerve is rarely reported. In the present study, we constructed a bionic microenvironment-inspired scaffold integrated with both anisotropic micro-nanocomposite topographies and IKVAV peptide. The results showed that both the topographies and peptide displayed good stability. The scaffolds could effectively induce the orientation growth of Schwann cells and up-regulate the genes and proteins relevant to myelination. Last, three signal pathways including the Wnt/ß-catenin pathway, the extracellular signal-regulated kinase/mitogen-activated protein pathway, and the transforming growth factor-ß pathway were put forward, revealing the main path of synergistic effects of anisotropic micro-nanocomposite topographies and biological cues on neuroregeneration. The present study may supply an important strategy for developing functional of artificial nerve implants.