Upper Critical Solution Temperature Polyvalent Scaffolds Aggregate and Exterminate Bacteria.

Specific recognition and strong affinities of bacteria receptors with the host cell glycoconjugates pave the way to control the bacteria aggregation and kill bacteria. Herein, using aggregation-induced emission (AIE) molecules decorated upper critical solution temperature (UCST) polyvalent scaffold (PATC-GlcN), an approach toward visualizing bacteria aggregation and controlling bacteria-polyvalent scaffolds affinities under temperature stimulus is described. Polyvalent scaffolds with diblocks, one UCST block PATC of polyacrylamides showing a sharp UCST transition and typical AIE behavior, the second bacteria recognition block GlcN of hydrophilic glucosamine modified polyacrylamide, are prepared through a reversible addition and fragmentation chain transfer polymerization. Aggregated chain conformation of polyvalent scaffolds at temperature below UCST induces the aggregation of E. coli ATCC8739, because of the high density of glucosamine moieties, whereas beyond UCST, the hydrophilic state of the scaffolds dissociates the bacteria aggregation. The sweet-talking of bacteria toward the polyvalent scaffolds can be visualized by the fluorescent imaging technique, simultaneously. Due to the specific recognition of polyvalent scaffolds with bacteria, the photothermal agent IR780 loaded PATC-GlcN shows the targeted killing ability toward E. coli ATCC8739 in vitro and in vivo under NIR radiation.

Polypseudorotaxanes Derived from Tetraphenylethylene: Preparation and Tandem-Activated Aggregation-Induced Emission.

Tuning the fluorescence of aggregation-induced emission (AIE)-based materials in a reversible way is essential and a requisite for their applications. The multiple host-guest interactions of polypseudorotaxanes (PPRs) could alter the aggregation state of hydrophobic AIE-based polymeric materials and consequently switch the fluorescence. Herein, tetraphenylethylene (TPE) as a typical AIE molecule has been incorporated into the main chains of the guest polyurethane via a step condensation between poly(ethylene glycol) (PEG)-based dicarbonate and TPE-diamine along with the cleavable disulfide bonds. γ-Cyclodextrins (γ-CDs) can selectively recognize the TPE units at the polyurethane chains to afford a PPR. Hydrophilic PEG segments and γ-CD molecules in the PPR could promote the disaggregation of TPE units, suppressing the fluorescence emission of TPE. To restore the aggregated state and fluorescence of TPE units, tris(2-carboxyethyl)phosphine (TCEP) and α-amylase are sequentially introduced to cleave the disulfide bonds and cut α-1,4 glycosidic bonds of γ-CD, reactivating the AIE behavior of PPR tandemly and accomplishing the reversible cycle of tuning the fluorescence of TPE. The present study provides a tandem way to switch the AIE behavior of polymeric materials reversibly.

Self-Healing Hydrogels of Low Molecular Weight Poly(vinyl alcohol) Assembled by Host-Guest Recognition.

Poly(vinyl alcohol) (PVA) is a cytocompatible synthetic polymer and has been commonly used to prepare hydrogels. Bile acids and ß-cyclodextrin are both natural compounds and they form stable host-guest inclusion complexes. They are attached covalently onto a low molecular weight PVA separately. Self-healing hydrogels can be easily formed by mixing the aqueous solutions of these PVA based polymers. The mechanical properties of the hydrogels can be tuned by varying the molar fractions of bile acid units on PVA. The dynamic inclusion complexation of the host-guest pair of the hydrogel allows the self-healing rapidly under ambient atmosphere and their mechanical properties could recover their original values in 1 min after incision. These PVA based polymers exhibited the good cytocompatibility and high hemocompatibility as shown by their biological evaluations. The use of natural compounds for host-guest interaction make such gels especially convenient to use as biomaterials, an advantage over conventional hydrogels prepared through freeze-thaw method.

Glycopolymers Bearing Galactose and Betulin: Synthesis, Encapsulation, and Lectin Recognition.

Betulin is a natural triterpene compound with anticarcinogen and antiviral activities. It is conjugated with methacrylate and then copolymerized with a galactose-bearing comonomer by RAFT polymerization to yield both random and block copolymers. These glycopolymers are designed to possess similar molecular weights and monomer compositions for easy comparison. They self-assembled into micelles, as shown by dynamic light scattering (DLS) and transmission electron microscopy. The smaller micelles formed by the random copolymers facilitated the encapsulation of Nile Red and released more of this hydrophobic model compound (46% in 4 days versus 32% released from the block copolymers). These glycopolymers interacted with lectins, such as RCA120, as studied by turbidity assay and DLS. The block copolymers formed larger aggregates and clustered faster than the random copolymers. The betulin-based glycopolymers may serve as biocompatible multifunctional biomaterials and carriers for use in targeted release of drugs.

"Bitter-Sweet" Polymeric Micelles Formed by Block Copolymers from Glucosamine and Cholic Acid.

Natural compounds glucosamine and cholic acid have been used to make acrylic monomers which are subsequently used to prepare amphiphilic block copolymers by reversible addition-fragmentation chain transfer (RAFT) polymerization. Despite the striking difference in polarity and solubility, three diblock copolymers consisting of glucosamine and cholic acid pendants with different hydrophilic and hydrophobic chain lengths have been synthesized without the use of protecting groups. They are shown to self-assemble into polymeric micelles with a "bitter" bile acid core and "sweet" sugar shell in aqueous solutions, as evidenced by dynamic light scattering and transmission electron microscopy. The critical micelle concentration varies with the hydrophobic/hydrophilic ratio, ranging from 0.62 to 1.31 mg/L. Longer chains of polymers induced the formation of larger micelles in range of 50-70 nm. These micelles can solubilize hydrophobic compounds such as Nile Red in aqueous solutions. Their loading capacity mainly depends upon the hydrophobic/hydrophilic ratio of the polymers, and may be also related to the length of the hydrophilic block. These polymeric micelles allowed for a 10-fold increase in the aqueous solubility of paclitaxel and showed no cytotoxicity below the concentration of 500 mg/L. Such properties make these polymeric micelles interesting reservoirs for hydrophobic molecules and drugs for biomedical applications.

Block and random copolymers bearing cholic acid and oligo(ethylene glycol) pendant groups: aggregation, thermosensitivity, and drug loading.

A series of block and random copolymers consisting of oligo(ethylene glycol) and cholic acid pendant groups were synthesized via ring-opening metathesis polymerization of their norbornene derivatives. These block and random copolymers were designed to have similar molecular weights and comonomer ratios; both types of copolymers showed thermosensitivity in aqueous solutions with similar cloud points. The copolymers self-assembled into micelles in water as shown by dynamic light scattering and transmission electron microscopy. The hydrodynamic diameter of the micelles formed by the block copolymer is much larger and exhibited a broad and gradual shrinkage from 20 to 54 °C below its cloud point, while the micelles formed by the random copolymers are smaller in size but exhibited some swelling in the same temperature range. Based on in vitro drug release studies, 78% and 24% paclitaxel (PTX) were released in 24 h from micelles self-assembled by the block and random copolymers, respectively. PTX-loaded micelles formed by the block and random copolymers exhibited apparent antitumor efficacy toward the ovarian cancer cells with a particularly low half-maximal inhibitory concentration (IC50) of 27.4 and 40.2 ng/mL, respectively. Cholic acid-based micelles show promise as a versatile and potent platform for cancer chemotherapy.

Main-Chain Cationic Bile Acid Polymers Mimicking Facially Amphiphilic Antimicrobial Peptides.

Antibiotic-resistant bacterial infections have led to an increased demand for antibacterial agents that do not contribute to antimicrobial resistance. Antimicrobial peptides (AMPs) with the facially amphiphilic structures have demonstrated remarkable effectiveness, including the ability to suppress antibiotic resistance during bacterial treatment. Herein, inspired by the facially amphiphilic structure of AMPs, the facially amphiphilic skeletons of bile acids (BAs) are utilized as building blocks to create a main-chain cationic bile acid polymer (MCBAP) with macromolecular facial amphiphilicity via polycondensation and a subsequent quaternization. The optimal MCBAP displays an effective activity against Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative Escherichia coli, fast killing efficacy, superior bactericidal stability in vitro, and potent anti-infectious performance in vivo using the MRSA-infected wound model. MCBAP shows the low possibility to develop drug-resistant bacteria after repeated exposure, which may ascribe to the macromolecular facial amphiphilicity promoting bacterial membrane disruption and the generation of reactive oxygen species. The easy synthesis and low cost of MCBAP, the superior antimicrobial performance, and the therapeutic potential in treating MRSA infection altogether demonstrate that BAs are a promising group of building blocks to mimic the facially amphiphilic structure of AMPs in treating MRSA infection and alleviating antibiotic resistance.

Marriage of High-Throughput Gradient Surface Generation With Statistical Learning for the Rational Design of Functionalized Biomaterials.

Functional biomaterial is already an important aspect in modern therapeutics; yet, the design of novel multi-functional biomaterial is still a challenging task nowadays. When several biofunctional components are present, the complexity that arises from their combinations and interactions will lead to tedious trial-and-error screening. In this work, a novel strategy of biomaterial rational design through the marriage of gradient surface generation with statistical learning is presented. Not only can parameter combinations be screened in a high-throughput fashion, but also the optimal conditions beyond the experimentally tested range can be extrapolated from the models. The power of the strategy is demonstrated in rationally designing an unprecedented ternary functionalized surface for orthopedic implant, with optimal osteogenic, angiogenic, and neurogenic activities, and its optimality and the best osteointegration promotion are confirmed in vitro and in vivo, respectively. The presented strategy is expected to open up new possibilities in the rational design of biomaterials.

Multi-responsive properties of a poly(ethylene glycol)-grafted alternating copolymers of distyrenic monomer with maleic anhydride.

A series of amphiphilic copolymers were synthesized by reversible addition-fragmentation chain transfer cyclocopolymerization of a styrenic monomer with maleic anhydride followed by grafting methoxy poly(ethylene glycol) onto the anhydride groups of the polymer chain. These amphiphilic graft copolymers exhibit multiple responsiveness toward temperature, pH, and selected cations in aqueous solutions. The cloud points (CP) of the graft copolymers increase with increasing length of the side chains and with increasing pH value of the solution. The addition of KCl and LiCl to the solutions had a salting-out effect lowering the CPs of the graft copolymers. The addition of NaCl, however, first raised the CP due to the complexation of the crown ether with Na(+) and then lowered the CP. The light scattering results confirmed an increase in phase transition temperature at lower concentrations of NaCl (5 and 10 mM) and then a decrease at a higher concentration of the sodium salt (100 mM).

Macroporous Adhesive Nano-Enabled Hydrogels Generated from Air-in-Water Emulsions.

Developing nanocomposite hydrogel with multi-functions including adjustable mechanical property, tissue-adhesion, and blood coagulation property to accelerate wound healing is highly desirable in surgical application. Here a macroporous adhesive nano-enabled hydrogel constructed from gelatin methacryloyl stabilized air-in-water emulsions incorporated with dopamine-grafted-gelatin (GelDA) and Laponite nanoclay is reported. The hydrogel exhibits interconnected macroporous structure. The physical/chemical cross-linked network formed among the various components contributes to the good mechanical strength of hydrogel, which could be further regulated by adjusting the concentration of Laponite nanoclay. Furthermore, the nanocomposite macroporous hydrogel is endowed with self-healing properties and tissue adhesion by the intermolecular hydrogen bonds, ionic interactions among Laponite nanoclay and polymers, as well as the catechol functional groups. The in vitro studies demonstrate that the macroporous hydrogel has good biocompatibility and could significantly reduce blood clotting time, which is expected to be applied for the rapid sealing and hemostasis of bleeding wounds.

Polypeptide-based self-healing hydrogels: Design and biomedical applications.

Self-healing hydrogels can heal themselves on the damaged sites, which opens up a fascinating way for enhancing lifetimes of materials. Polypeptide/poly(amino acid) is a class of polymers in which natural amino acid monomers or derivatives are linked by amide bonds with a stable and similar secondary structure as natural proteins (α-helix or ß-fold). They have the advantages of nontoxicity, biodegradability, and low immunogenicity as well as easy modification. All these properties make polypeptides extremely suitable for the preparation of self-healing hydrogels for biomedical applications. In this review, we mainly focus on the progress in the fabrication strategies of polypeptide-based self-healing hydrogels and their biomedical applications in the recent 5 years. Various crosslinking methods for the preparation of polypeptide-based self-healing hydrogels are first introduced, including host-guest interactions, hydrogen bonding, electrostatic interactions, supramolecular self-assembly of ß-sheets, and reversible covalent bonds of imine and hydrazone as well as molecular multi-interactions. Some representative biomedical applications of these self-healing hydrogels such as delivery system, tissue engineering, 3D-bioprinting, antibacterial and wound healing as well as bioadhesion and hemostasis are also summarized. Current challenges and perspectives in future for these "smart" hydrogels are proposed at the end . STATEMENT OF SIGNIFICANCE: Polypeptides with the advantages of nontoxicity, biodegradability, hydrophilicity and low immunogenicity, are extremely suitable for the preparation of self-healing hydrogels in biomedical applications. Recently, the researches of polypeptide-based self-healing hydrogel have drawn the great attentions for scientists and engineers. A review to summarize the recent progress in design and biomedical applications of these polypeptide-based self-healing hydrogels is highly needed. In this review, we mainly focus on the progress in fabrication strategies of polypeptide-based self-healing hydrogels and biomedical applications in recent five years and aim to draw the increased attention to the importance of these "smart" hydrogels, facilitating the advances in biomedical applications. We believe this work would draw interest from readers of Acta Biomaterialia.

Conductive and antimicrobial macroporous nanocomposite hydrogels generated from air-in-water Pickering emulsions for neural stem cell differentiation and skin wound healing.

Electro-active conducting hydrogels have shown promising applications in promoting soft tissue regeneration. However, achieving good conductive performance while simultaneously imparting macroporous structures to these hydrogels still remains challenging. In this study, we report the development of multifunctional conductive macroporous nanocomposite hydrogels (MNHs) prepared by an air-in-water emulsion template that is stabilized by colloidal hybrids of carbon nanotubes (CNTs) and gelatin methacryloyl. The MNH hydrogels demonstrated tunable pore size, electrical conductivity and mechanical properties with various CNT concentrations in the crosslinking matrices. An in vitro cell assay showed that the MNH hydrogels could promote the spreading and differentiation of NE-4C neural stem cells. Furthermore, sustainable release of antimicrobial peptides (AMPs) from the MNH hydrogel can be achieved and the released AMPs maintained high S. aureus killing activity. An in vivo evaluation of the MNH hydrogel using a murine dorsal skin model further showed that the conductive MNH hydrogel loaded with AMPs demonstrated appealing antimicrobial and wound healing performance in two weeks.

TiO2 and PEEK Reinforced 3D Printing PMMA Composite Resin for Dental Denture Base Applications.

The future of manufacturing applications in three-dimensional (3D) printing depends on the improvement and the development of materials suitable for 3D printing technology. This study aims to develop an applicable and convenient protocol for light-curing resin used in 3D industry, which could enhance antibacterial and mechanical properties of polymethyl methacrylate (PMMA) resin through the combination of nano-fillers of surface modified titanium dioxide (TiO2) and micro-fillers of polyetheretherketone (PEEK). PMMA-based composite resins with various additions of TiO2 and PEEK were prepared and submitted to characterizations including mechanical properties, distribution of the fillers (TiO2 or/and PEEK) on the fractured surface, cytotoxicity, antibacterial activity, and blood compatibility assessment. These results indicated that the reinforced composite resins of PMMA (TiO2-1%-PEEK-1%) possessed the most optimized properties compared to the other groups. In addition, we found the addition of 1% of TiO2 would be an effective amount to enhance both mechanical and antibacterial properties for PMMA composite resin. Furthermore, the model printed by PMMA (TiO2-1%-PEEK-1%) composite resin showed a smooth surface and a precise resolution, indicating this functional dental restoration material would be a suitable light-curing resin in 3D industry.

A Study of 3D-Printable Reinforced Composite Resin: PMMA Modified with Silver Nanoparticles Loaded Cellulose Nanocrystal.

With the rapid application of light-curing 3D printing technology, the demand for high-performance polymer resins is increasing. Existing light-curable resins often have drawbacks limiting their clinical applications. This study aims to develop a new type of polymethyl methacrylate (PMMA) composite resins with enhanced mechanical properties, high antibacterial activities and excellent biocompatibilities. A series of reinforced composite resins were prepared by mechanically mixing PMMA with modified cellulose nanocrystals (CNCs), which were coated with polydopamine and decorated by silver nanoparticles (AgNPs) via Tollen reaction. The morphology of CNCs-Ag was observed by transmission electron microscopy and the formation of AgNPs on CNCs was confirmed by X-Ray photoelectron spectroscopy analyses. Functional groups in PMMA-CNCs-Ag composites were verified by Fourier Transform infrared spectroscopy (FTIR) spectroscopy. The mechanical assessment and scanning electron microscopy analysis suggested that the evenly distributed CNCs-AgNPs composite effectively improve mechanical properties of PMMA resin. Cytotoxicity assay and antibacterial activity tests indicated excellent biocompatibility and high antibacterial activities. Furthermore, PMMA with CNCs-AgNPs of 0.1 wt.% (PMMA-CNCs-AgNPs-0.1) possessed the most desirable mechanical properties owing to the homogeneous distribution of AgNPs throughout the resin matrix. This specific composite resin can be used as a functional dental restoration material with potential of other medical applications.

Thermo- and pH-Responsive Copolymers Bearing Cholic Acid and Oligo(ethylene glycol) Pendants: Self-Assembly and pH-Controlled Release.

A family of block and random copolymers of norbornene derivatives bearing cholic acid and oligo(ethylene glycol) pendants were prepared in the presence of Grubbs' catalyst. The phase transition temperature of the copolymers in aqueous solutions may be tuned by the variation of comonomer ratios and pH values. Both types of copolymers formed micellar nanostructures with a hydrophilic poly(ethylene glycol) shell and a hydrophobic core containing cholic acid residues. The micellar size increased gradually with increasing pH due to the deprotonation of the carboxylic acid groups. These micelles were capable of encapsulating hydrophobic compounds such as Nile Red (NR). A higher hydrophobicity/hydrophilicity ratio in both copolymers resulted in a higher loading capacity for NR. With similar molecular weights and monomer compositions, the block copolymers showed a higher loading capacity for NR than the random copolymers. The NR-loaded micelles exhibited a pH-triggered release behavior. At pH 7.4 within 96 h, the micelles formed by the block and random of copolymers released 56 and 97% NR, respectively. Therefore, these micelles may have promise for use as therapeutic nanocarriers in drug delivery systems.