Surface hydrophobization of hydrogels via interface dynamics-induced network reconfiguration.

Effective and easy regulation of hydrogel surface properties without changing the overall chemical composition is important for their diverse applications but remains challenging to achieve. We report a generalizable strategy to reconfigure hydrogel surface networks based on hydrogel-substrate interface dynamics for manipulation of hydrogel surface wettability and bioadhesion. We show that the grafting of hydrophobic yet flexible polymeric chains on mold substrates can significantly elevate the content of hydrophobic polymer backbones and reduce the presence of polar groups in hydrogel surface networks, thereby transforming the otherwise hydrophilic hydrogel surface into a hydrophobic surface. Experimental results show that the grafted highly dynamic hydrophobic chains achieved with optimal grafting density, chain length, and chain structure are critical for such substantial hydrogel surface network reconfiguration. Molecular dynamics simulations further reveal the atomistic details of the hydrogel network reconfiguration induced by the dynamic interface interactions. The hydrogels prepared using our strategy show substantially enhanced bioadhesion and transdermal delivery compared with the hydrogels of the same chemical composition but fabricated via the conventional method. Our findings provide important insights into the dynamic hydrogel-substrate interactions and are instrumental to the preparation of hydrogels with custom surface properties.

Supramolecular Hydrogel with Ultra-Rapid Cell-Mediated Network Adaptation for Enhancing Cellular Metabolic Energetics and Tissue Regeneration.

Cellular energetics plays an important role in tissue regeneration, and the enhanced metabolic activity of delivered stem cells can accelerate tissue repair and regeneration. However, conventional hydrogels with limited network cell adaptability restrict cell-cell interactions and cell metabolic activities. In this work, it is shown that a cell-adaptable hydrogel with high network dynamics enhances the glucose uptake and fatty acid ß-oxidation of encapsulated human mesenchymal stem cells (hMSCs) compared with a hydrogel with low network dynamics. It is further shown that the hMSCs encapsulated in the high dynamic hydrogels exhibit increased tricarboxylic acid (TCA) cycle activity, oxidative phosphorylation (OXPHOS), and adenosine triphosphate (ATP) biosynthesis via an E-cadherin- and AMP-activated protein kinase (AMPK)-dependent mechanism. The in vivo evaluation further showed that the delivery of MSCs by the dynamic hydrogel enhanced in situ bone regeneration in an animal model. It is believed that the findings provide critical insights into the impact of stem cell-biomaterial interactions on cellular metabolic energetics and the underlying mechanisms.

Highly Stretchable, Self-Healing, Injectable and pH Responsive Hydrogel from Multiple Hydrogen Bonding and Boron-Carbohydrate Interactions.

A simple and cost-effective method for the fabrication of a safe, dual-responsive, highly stretchable, self-healing and injectable hydrogel is reported based on a combination of dynamic boronate ester bonds and hydrogen bonding interactions. The mechanical properties of the hydrogel are tunable by adjusting the molar ratios between sugar moieties on the polymer and borax. It was remarkable to note that the 2:1 ratio of sugar and borate ion significantly improves the mechanical strength of the hydrogel. The injectability, self-healing and stretchability properties of the hydrogel were also examined. In addition, the impact of the variation of the pH and the addition of free sugar responsiveness of the hydrogel was studied. High MRC-5 cell viability was noticed by the 3D live/dead assay after 24 h cell culture within the hydrogel scaffold. Hence, the developed hydrogels have desirable features that warrant their applications for drug delivery, scaffolds for cell and tissue engineering.

Water-Immiscible Coacervate as a Liquid Magnetic Robot for Intravascular Navigation.

Developing magnetic ultrasoft robots to navigate through extraordinarily narrow and confined spaces like capillaries in vivo requires synthesizing materials with excessive deformability, responsive actuation, and rapid adaptability, which are difficult to achieve with the current soft polymeric materials, such as elastomers and hydrogels. We report a magnetically actuatable and water-immiscible (MAWI) coacervate based on the assembled magnetic core-shell nanoparticles to function as a liquid robot. The degradable and biocompatible millimeter-sized MAWI coacervate liquid robot can remain stable under changing pH and salt concentrations, release loaded cargoes on demand, squeeze through an artificial capillary network within seconds, and realize intravascular targeting in vivo guided by an external magnetic field. We believe the proposed "coacervate-based liquid robot" can implement demanding tasks beyond the capability of conventional elastomer or hydrogel-based soft robots in the field of biomedicine and represents a distinct design strategy for high-performance ultrasoft robots.

Glycopolymer-Cell-Penetrating Peptide (CPP) Conjugates for Efficient Epidermal Growth Factor Receptor (EGFR) Silencing.

Overexpression of epidermal growth factor receptor (EGFR) is observed in multiple cancers such as colorectal, lung, and cervical solid tumors. Regulating the EGFR expression is an efficient strategy to manage these malignancies, and it can be achieved by using short interfering RNA (siRNA). Cell-penetrating peptides (CPPs) demonstrated an excellent capability to enhance the cellular uptake of siRNA, but high knockdown efficiencies have not been achieved due to endosomal entrapment. In this work, Schiff's base reaction was used to modify a block {P[LAEMA(2-lactobionamidoethyl methacrylamide)37]-b-P[FPMA(4-formyl phenyl methacrylate)2-st-DMA(N,N-dimethylacrylamide)2], P2} and two statistical [P(LAEMA23-st-FPMA3) (P3) and P(LAEMA25-st-FPMA2-st-DMA2) (P4)] aldehyde-based and galactose-based polymers, prepared via reversible addition-fragmentation chain-transfer (RAFT) polymerization. An arginine-rich peptide (ARP, KRRKRRRRRK) was used as a cell-penetrating peptide (CPP) and conjugated to the polymers via a Schiff base reaction. The resulting glycopolymer-peptide conjugates were utilized to condense the siRNA to prepare polyplexes with multivalent CPPs (MCPPs, a nanoparticle with multiple copies of the CPP) to enhance the endosomal escape. The polyplexes have different surface properties as determined by the architecture of polymers and the insertion of dimethyl amide moieties. The enhancement of cellular internalization of ARP was observed by labeling the polyplexes with fluorescein isothiocyanate (FITC)-siRNA showing a localization of polyplexes in the cytoplasm of a HeLa (cervical cancer) cell line. In the in vitro EFGR silencing study, the statistical glycopolymer-peptide (P3-P) polyplexes had superior EGFR silencing efficiency in comparison with the other polymers that were studied. Furthermore, P3-P polyplexes led to less off-targeting silencing than lipofectamine 3000. These encouraging results confirmed the potency of decorating galactose-based polymers with CPP, like ARP for their application in siRNA delivery and management of cervical carcinomas.

Temperature-Responsive Aldehyde Hydrogels with Injectable, Self-Healing, and Tunable Mechanical Properties.

Injectable and self-healing hydrogels with exemplary biocompatibility and tunable mechanical properties are urgently needed due to their significant advantages for tissue engineering applications. Here, we report a new temperature-responsive aldehyde hydrogel with dual physical-cross-linked networks and injectable and self-healing properties prepared from an ABA-type triblock copolymer, poly{[FPMA(4-formylphenyl methacrylate)-co-DEGMA[di(ethylene glycol) methyl ether methacrylate]-b-MPC(2-methacryloyloxyethyl phosphorylcholine)-b-(FPMA-co-DEGMA)}. The thermoresponsive poly(DEGMA) segments drive the dehydration and hydrophobic interaction, enabling polymer chain winding as the first cross-linking network, when the temperature is raised above the critical gelation temperature. Meanwhile, the benzaldehyde groups offer physical interactions, including hydrogen bonding and hydrophobic and π-π stacking interactions as the second cross-linking network. When increasing the benzaldehyde content in the triblock copolymers from 0 to 8.2 mol %, the critical gelation temperature of the resulted hydrogels dropped from 35.5 to 19.9 °C and the mechanical modulus increased from 21 to 1411 Pa. Owing to the physical-cross-linked networks, the hydrogel demonstrated excellent injectability and self-healing properties. The cell viabilities tested from MTT assays toward both normal lung fibroblast cells (MRC-5) and cancerous cervical (HeLa) cells were found to be 100 and 101%, respectively, for varying polymer concentrations up to 1 mg/mL. The 3D cell encapsulation of the hydrogels was evaluated by a cytotoxicity Live/Dead assay, showing 92% cell viability. With these attractive physiochemical and biological properties, this temperature-responsive aldehyde hydrogel can be a promising candidate as a cell scaffold for tissue engineering.

Zwitterionic Block Copolymer Prodrug Micelles for pH Responsive Drug Delivery and Hypoxia-Specific Chemotherapy.

Tirapazamine (TPZ) and its derivatives (TPZD) have shown their great potential for efficiently killing hypoxic cancer cells. However, unsatisfactory clinical outcomes resulting from the low bioavailability of the low-molecular TPZ and TPZD limited their further applications. Precise delivery and release of these prodrugs via functional nanocarriers can significantly improve the therapeutic effects due to the targeted drug delivery and enhanced permeability and retention (EPR) effect. Herein, zwitterionic block copolymer (BCP) micelles with aldehyde functional groups are prepared from the self-assembly of poly(2-methacryloyloxyethyl phosphorylcholine-b-poly(di(ethylene glycol) methyl ether methacrylate-co-4-formylphenyl methacrylate) [PMPC-b-P(DEGMA-co-FPMA)]. TPZD is then grafted onto PMPC-b-P(DEGMA-co-FPMA) to obtain a polymer-drug conjugate, PMPC-b-P(DEGMA-co-FPMA-g-TPZD) (BCP-TPZ), through the formation of a pH-responsive imine bond, exhibiting a pH-dependent drug release profile owing to the cleavage of the imine bond under acidic conditions. Outstandingly, BCP-TPZ shows around 13.7-fold higher cytotoxicity to hypoxic cancer cells in comparison to normoxic cancer cells evaluated through an in vitro cytotoxicity assay. The pH-responsiveness and hypoxia-specific cytotoxicity confer BCP-TPZ micelles a great potential to achieve precise delivery of TPZD and thus enhance the therapeutic effect toward tumor-hypoxia.

Dual-Cross-Linked Network Hydrogels with Multiresponsive, Self-Healing, and Shear Strengthening Properties.

Dual-cross-linked network (DCN) hydrogels with multiresponsive and self-healing properties are attracting intensive interests due to their enhanced mechanical strength for a wide range of applications. Herein, we developed a DCN hydrogel that combines a dynamic imine and a benzoxaboronic ester with a neutral pKa value (∼7.2) as dual linkages and contains biocompatible zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) [poly(MPC)] as the backbone. Oscillatory rheology result indicated shear strengthening mechanical properties compared to the single-cross-linked network (SCN) hydrogels, which use either imine bond or benzoxaboronic ester as the linkage alone. Due to the coexistence of stimuli-responsive imine and benzoxaboronic ester, the DCN hydrogels show sensitive multiple responsiveness to pH, sugar, and hydrogen peroxide. The dynamic nature of the dual linkages endows the DCN hydrogels with excellent self-healing ability after fracture. More importantly, the excellent biocompatibility and performance in three-dimensional (3D) cell encapsulation were established by a cytotoxicity Live/Dead assay, indicating DCN hydrogel's great potential as a cell culture scaffold. The biocompatible poly(MPC)-based backbone and the rapid formation of the cross-linking network make the DCN hydrogels promising candidates for future biomedical applications.

Preparation and Characterization of Thermoresponsive PEG-Based Injectable Hydrogels and Their Application for 3D Cell Culture.

We report here the synthesis of a series of ethylene glycol-based triblock copolymers containing a hydrophilic middle segment of poly(ethylene glycol) methyl ether methacrylate (PEGMA) and two temperature-responsive segments of diethylene glycol methyl ether methacrylate (DEGMA) at both ends via the reversible addition-fragmentation chain-transfer (RAFT) polymerization. While the corresponding temperature-responsive homopolymer (PDEGMA) and the diblock copolymer (PDEGMA-b-PPEGMA) could not form a gel, the triblock copolymers (PDEGMA-b-PPEGMA-b-PDEGMA) could form a physical gel at certain concentrations and at temperatures above the lower critical solution temperature (LCST). This sol-gel transition is fully reversible and can be repeated several times. Depending on the chain length of the middle block and two end blocks, a physical gel could be formed at a minimum polymer concentration of 5 wt %. In addition, a mechanically strong gel could be easily formed within 5 s at the maximum concentration of 20 wt % and at a temperature of 37 °C. Considering the good cell compatibility and soft rubbery nature of the triblock copolymers, they can potentially be used as injectable scaffold for cell culture and tissue engineering applications.

Facile Preparation of Macromolecular Prodrugs for Hypoxia-Specific Chemotherapy.

Hypoxia-activated prodrugs (HAPs) have emerged as important candidates for chemotherapy due to their efficient killing of hypoxic cancer cells. Traditional small molecule agents, such as tirapazamine (TPZ) and its derivatives, have shown unsatisfactory therapeutic effect in clinical trials due to poor bioavailability in hypoxic tumor regions. Herein, an amphiphilic macromolecular prodrug with hypoxia-specific activity, named as hypoxia-activated macromolecular prodrug (HAMP), is prepared from poly{[poly(ethylene glycol) methacrylate]-st-(methacrylic acid)} [poly(PEGMA-st-MAA)], containing pendant TPZ residues. This polymer can self-assemble in an aqueous system into ∼37 nm sized nanoparticles. In vitro experiments indicated that HAMP shows 5× higher cytotoxicity to hypoxic cancer cells as compared to normoxic cancer cells. Therefore, the developed HAMP can be concurrently used with other therapeutic agents as a highly efficient hypoxia-activated agent.

An efficient heterogeneous signcryption for smart grid.

A smart grid, considered the next-generation type of power grid, combines a traditional power grid with information and communication technologies to effectively facilitate power generation and ensure transmission security and reliability in real-time. Only authorized consumers should be able to access the smart grid because the information gathered by smart meters includes users' private information. However, smart grid security is still a challenge. Motivated by this challenge, in this paper, we propose a heterogeneous signcryption (HSC) scheme for secure communication between smart meters and the utility. We demonstrate that this scheme is indistinguishable against adaptive chosen-ciphertext attacks (IND-CCA2), existentially unforgeable against adaptive chosen-message attacks (EUF-CMA) and ciphertext-anonymous against adaptive chosen ciphertext attacks (ANON-CCA2) under the computational Diffie-Hellman (CDH) problem in the random oracle model. Our scheme simultaneously achieves confidentiality, integrity, authentication, non-repudiation and ciphertext anonymity in a single logical step. It supports heterogeneous systems, allowing a meter in an identity-based cryptography (IBC) environment to transmit electrical usage data to a utility in a public key infrastructure (PKI) environment. Compared with other existing related schemes, our scheme has the lowest communication overhead and energy consumption for the smart grid. Based on these features, our scheme is highly suitable for secure power transmissions in a smart grid.

Quantifying Individual Brain Connectivity with Functional Principal Component Analysis for Networks.

In typical functional connectivity studies, connections between voxels or regions in the brain are represented as edges in a network. Networks for different subjects are constructed at a given graph density and are summarized by some network measure such as path length. Examining these summary measures for many density values yields samples of connectivity curves, one for each individual. This has led to the adoption of basic tools of functional data analysis, most commonly to compare control and disease groups through the average curves in each group. Such group differences, however, neglect the variability in the sample of connectivity curves. In this article, the use of functional principal component analysis (FPCA) is demonstrated to enrich functional connectivity studies by providing increased power and flexibility for statistical inference. Specifically, individual connectivity curves are related to individual characteristics such as age and measures of cognitive function, thus providing a tool to relate brain connectivity with these variables at the individual level. This individual level analysis opens a new perspective that goes beyond previous group level comparisons. Using a large data set of resting-state functional magnetic resonance imaging scans, relationships between connectivity and two measures of cognitive function-episodic memory and executive function-were investigated. The group-based approach was implemented by dichotomizing the continuous cognitive variable and testing for group differences, resulting in no statistically significant findings. To demonstrate the new approach, FPCA was implemented, followed by linear regression models with cognitive scores as responses, identifying significant associations of connectivity in the right middle temporal region with both cognitive scores.

The Asn680Ser polymorphism of the follicle stimulating hormone receptor gene and ovarian cancer risk: a meta-analysis.

PURPOSE: The purpose of this study was to conduct a meta-analysis to assess the association between FSHR Asn680Ser polymorphism and ovarian cancer susceptibility. METHODS: A literature search was conducted in PubMed, Embase and the China National Knowledge Infrastructure (CNKI) for all relevant studies published up to September 2013. The pooled odds ratios (ORs) with the corresponding 95 % confidence intervals (95 % CIs) were calculated to evaluate the association. RESULTS: Four case-control studies including 474 ovarian cancer cases and 659 controls met the inclusion criteria. The pooled analyses showed that FSHR Asn680Ser polymorphism was associated with the risk of ovarian cancer (Ser vs Asn: OR=1.295, 95 % CI 1.057-1.498, P=0.01; Ser/Ser + Asn/Ser vs Asn/Asn: OR=1.611, 95 % CI 1.027-2.528, P=0.038). Subgroup analyses by ethnicity (Caucasian and Asian) further revealed significant associations among Asians (Ser vs Asn: OR=1.386, 95 % CI 1.066-1.802, P=0.015; Ser/Ser + Asn/Ser vs Asn/Asn: OR=1.893, 95 % CI 1.329-2.689, P=0.000) but not Caucasians. There was no obvious risk of publication bias. CONCLUSIONS: The meta-analysis suggests that FSHR Asn680Ser polymorphism may be a risk factor for ovarian cancer in Asians. Due to the limited quantity of the included studies, further studies are needed to validate the above conclusions.

Reliability of environmental sampling culture results using the negative binomial intraclass correlation coefficient.

The Intraclass Correlation Coefficient (ICC) is commonly used to estimate the similarity between quantitative measures obtained from different sources. Overdispersed data is traditionally transformed so that linear mixed model (LMM) based ICC can be estimated. A common transformation used is the natural logarithm. The reliability of environmental sampling of fecal slurry on freestall pens has been estimated for Mycobacterium avium subsp. paratuberculosis using the natural logarithm transformed culture results. Recently, the negative binomial ICC was defined based on a generalized linear mixed model for negative binomial distributed data. The current study reports on the negative binomial ICC estimate which includes fixed effects using culture results of environmental samples. Simulations using a wide variety of inputs and negative binomial distribution parameters (r; p) showed better performance of the new negative binomial ICC compared to the ICC based on LMM even when negative binomial data was logarithm, and square root transformed. A second comparison that targeted a wider range of ICC values showed that the mean of estimated ICC closely approximated the true ICC.

Isolation and characterization of human anti-VEGF165 monoclonal antibody with anti-tumor efficacy from transgenic mice expressing human immunoglobulin loci.

The purpose of this study was to prepare a fully human anti-VEGF (vascular endothelial growth factor) monoclonal antibody with anti-tumor activity from five-feature mice which express human immunoglobin loci. Four hybridomas secreting mAb stably were isolated successfully. Some characters such as isotypes, cross-reactivity, inhibition on the binding of hVEGF to VEGFR-2, dissociation constants and the idiotypic characteristic were determined. Proliferation of T24 and Ls-174-T cell line and nude mice bearing human colorectal cancer were used to evaluate therapeutic effects and safety of this mAb. Pharmacokinetics data shows the half life of this mAb was about 5 days after a single intravenous injection. These results suggest the fully human anti-VEGF mAb maybe safe and efficient for cancer treatment.

[Preparation and preliminary application of monoclonal antibody against recombinant human erythropoietin].

AIM: To prepare monoclonal antibody (mAb) against erythropoietin(EPO), characterize its biological properties and use it to purify the rhEPO from transgenic goat milk. METHODS: A crude rhEPO product was used as the antigen to immunize BALB/c mice for preparing mAbs against rhEPO. The mAbs were characterized by Western blot and indirect ELISA. Purified mAb 2E6 was coupled with pre-activated Sepharose 4B to prepare the immunoaffinity chromatography column for purifying the rhEPO from transgenic goat milk. RESULTS: Two hybridoma cell lines(1E7 and 2E6)were obtained. mAbs 1E7 and 2E6 were shown to be IgG1 and IgG2b respectively, and their light chains were both kappa. Western blot analysis confirmed that the two mAbs could bind to rhEPO. The immunoaffinity chromatography column could adsorb 70% of rhEPO in purifying the rhEPO from transgenic goat milk. CONCLUSION: Two hybridoma cell lines secreting anti-rhEPO mAbs were successfully established. The mAb-immunoaffinity chromatography column could be used to purify the rhEPO from transgenic goat milk.