Structural Element of Vitamin U-Mimicking Antibacterial Polypeptide with Ultrahigh Selectivity for Effectively Treating MRSA Infections.

Antimicrobial peptides (AMPs) exhibit mighty antibacterial properties without inducing drug resistance. Achieving much higher selectivity of AMPs towards bacteria and normal cells has always been a continuous goal to be pursued. Herein, a series of sulfonium-based polypeptides with different degrees of branching and polymerization were synthesized by mimicking the structure of vitamin U. The polypeptide, G2 -PM-1H+ , shows both potent antibacterial activity and the highest selectivity index of 16000 among the reported AMPs or peptoids (e.g., the known index of 9600 for recorded peptoid in "Angew. Chem. Int. Ed., 2020, 59, 6412."), which can be attributed to the high positive charge density of sulfonium and the regulation of hydrophobic chains in the structure. The antibacterial mechanisms of G2 -PM-1H+ are primarily ascribed to the interaction with the membrane, production of reactive oxygen species (ROS), and disfunction of ribosomes. Meanwhile, altering the degree of alkylation leads to selective antibacteria against either gram-positive or gram-negative bacteria in a mixed-bacteria model. Additionally, both in vitro and in vivo experiments demonstrated that G2 -PM-1H+ exhibited superior efficacy against methicillin-resistant Staphylococcus aureus (MRSA) compared to vancomycin. Together, these results show that G2 -PM-1H+ possesses high biocompatibility and is a potential pharmaceutical candidate in combating bacteria significantly threatening human health.

Water-Triggered Segment Orientation of Long-Lasting Anti-Biofouling Polyurethane Coatings on Biomedical Catheters via Solvent Exchange Strategy.

The formation of biofilm and thrombus on medical catheters poses a significant life-threatening concern. Hydrophilic anti-biofouling coatings upon catheter surfaces with complex shapes and narrow lumens are demonstrated to have the potential in reducing complications. However, their effectiveness is constrained by poor mechanical stability and weak substrate adhesion. Herein, a novel zwitterionic polyurethane (SUPU) with strong mechanical stability and long-term anti-biofouling is developed by controlling the ratio of sulfobetaine-diol and ureido-pyrimidinone. Once immersed in water, as-synthesized zwitterionic coating (SUPU3 SE) would undergo a water-driven segment reorientation to obtain much higher durability than its direct drying one, even under various extreme treatments, including acidic solution, abrasion, ultrasonication, flushing, and shearing, in PBS at 37 °C for 14 days. Moreover, SUPU3 SE coating could achieve a 97.1% of exceptional reducing protein fouling, complete prevention of cell adhesion, and long-lasting anti-biofilm performance even after 30 days. Finally, the good anti-thrombogenic formations of SUPU3 SE coating with bacterial treatment are validated in blood circulation through an ex vivo rabbit arteriovenous shunt model. This work provides a facile approach to fabricating stable hydrophilic coating through a simple solvent exchange to reduce thrombosis and infection of biomedical catheters.

Stimuli-responsive nanocarriers for bacterial biofilm treatment.

ABSTRACT: Bacterial biofilm infections have been threatening the human's life and health globally for a long time because they typically cause chronic and persistent infections. Traditional antibiotic therapies can hardly eradicate biofilms in many cases, as biofilms always form a robust fortress for pathogens inside, inhibiting the penetration of drugs. To address the issues, many novel drug carriers emerged as promising strategies for biofilm treatment. Among them, stimuli-responsive nanocarriers have attracted much attentions for their intriguing physicochemical properties, such as tunable size, shape and surface chemistry, especially smart drug release characteristic. Based on the microenvironmental difference between biofilm infection sites and normal tissue, many stimuli, such as bacterial products accumulating in biofilms (enzymes, glutathione, etc.), lower pH and higher H2O2 levels, have been employed and proved in favor of "on-demand" drug release for biofilm elimination. Additionally, external stimuli including light, heat, microwave and magnetic fields are also able to control the drug releasing behavior artificially. In this review, we summarized recent advances in stimuli-responsive nanocarriers for combating biofilm infections, and mainly, focusing on the different stimuli that trigger the drug release. 摘要: , , 。 , , 。 , , 。 , -, , , , 。 , , (, ), pHH2O2, ""。 , , , , 。 , , 。.

Transition of Conformation and Solubility in ß-Sheet-Structured Poly(l-cysteine)s with Methylthio or Sulfonium Pendants.

Poly(l-cysteine)s with methylthio pendants (PMTLCs) were synthesized by ring-opening polymerization of a new l-cysteine-based N-carboxyanhydride. The thioether bonds of PMTLC can be readily oxidized by H2O2 yielding water-soluble PMTLCOX. The methylthio groups can undergo an alkylation reaction using methyl iodide and a subsequent ion-exchange reaction yielding sulfonium-based polypeptides (PPLC-DMS-X, where X = I, BF4). PPLC-DMS-X showed upper critical solution temperature-type thermo- and oxidation-responsive properties in aqueous solutions. Both PMTLC and PPLC-DMS-X showed oxidation-induced ß-sheet to α-helix transitions. The absorbance of PPLC-DMS-I and methyl orange aqueous solution displayed a significant linear correlation with temperature, which makes the sulfonium-based polypeptides good candidates in the field of temperature sensors.

Single-Chain Nanoparticle-Based Coatings with Improved Bactericidal Activity and Antifouling Properties.

Dual-function antibacterial surfaces have exhibited promising potential in addressing implant-associated infections. However, both bactericidal and antifouling properties need to be further improved prior to practical uses. Herein, we report the preparation and properties of a linear block copolymer coating (LP-KF) and a single-chain nanoparticle coating (NP-KF) with poly(ethylene glycol) (PEG) and cationic polypeptide segments. NP-KF with cyclic PEG segments and densely charged polypeptide segments was expected to display improved bactericidal and antifouling properties. LP-KF was prepared by the combination of ring-opening polymerization of N-carboxyanhydride (NCA) monomers and subsequent deprotection. NP-KF was prepared by intramolecular cross-linking of LP-KF in diluted solutions. Both LP-KF- and NP-KF-coated PDMS surfaces were prepared by dipping with polydopamine-coated surfaces. They showed superior in vitro bactericidal activity against both Staphylococcus aureus and Escherichia coli with >99.9% killing efficacy, excellent protein adsorption resistance, antibacterial adhesion, and low cytotoxicity. The NP-KF coating showed higher bactericidal activity and antifouling properties than its linear counterpart. It also showed significant anti-infective property and histocompatibility in vivo, which makes it a good candidate for implants and biomedical device applications.

Facile Synthesis of Imidazolium-Based Block Copolypeptides with Excellent Antimicrobial Activity.

Antimicrobial polypeptides are promising mimics of antimicrobial peptides (AMPs) with low risks of antimicrobial resistance (AMR). Polypeptides with facile and efficient production, high antimicrobial activity, and low toxicity toward mammalian cells are highly desirable for practical applications. Herein, triblock copolypeptides with chloro groups (PPGn-PCPBLGm) and different main-chain lengths were synthesized via an ultrafast ring-opening polymerization (ROP) using a macroinitiator, namely poly(propylene glycol) bis(2-aminopropyl ether), and purified or nonpurified monomer (i.e., CPBLG-NCA). PPGn-PCPBLGm with 90 amino acid residues can be readily prepared within 300 s. Imidazolium-based block copolypeptides (PPGn-PILm) were facilely prepared via nucleophilic substitution of PPGn-PCPBLGm with NaN3 and subsequent "click" chemistry. α-Helical PPGn-PILm can self-assemble into nanostructured and cationic micelles which displayed highly potent antimicrobial activity and low hemolysis. The top-performing material, namely PPG34-PIL70, showed low minimum inhibitory concentration (MIC) against both Gram-positive S. aureus and Gram-negative E. coli (25 µg mL-1). It also displayed low toxicity against mouse embryonic fibroblast (NIH 3T3) and human embryonic kidney (293T) cells at 2× MIC.

Synthesis and Properties of Mono- or Diamine-Initiated Imidazolium-Based Cationic Polypeptides.

A series of cationic polypeptide imidazolium conjugates were prepared by ring-opening polymerization (ROP) of γ-4-(3-chloropropoxycarbonyl)benzyl-L- glutamic acid-based N-carboxyanhydride (CPBLG-NCA) initiated by various mono- or diamine initiators and subsequent side-chain modification with high grafting efficiency. Rapid and controlled ROP was achieved by polymerizing CPBLG-NCA in a dichloromethane/NaHCO3/H2O solvent mixture with the amine initiators. The resulting polypeptides bearing imidazolium iodide pendants showed reversible upper critical solution temperature (UCST)-type thermoresponsive properties in both ethanol and DI water while the polypeptides with tetrafluoroborate counter-anions showed a UCST in phosphate buffer saline (PBS). The cloud point temperature (Tcp) in ethanol and aqueous solutions can be tuned by both molecular weight and the end- or linkage-groups in the main chain. The cationic polypeptides showed good antibacterial activity against Staphylococcus aureus and low hemolysis. Our results provide a facile and rapid ROP strategy to develop new families of stimuli-responsive polypeptides with tunable properties as well as antibacterial polypeptides with optimized selectivity.

Hierarchical Polymer Brushes with Dominant Antibacterial Mechanisms Switching from Bactericidal to Bacteria Repellent.

Although polycationic surfaces have high antimicrobial efficacies, they suffer from high toxicity to mammalian cells and severe surface accumulation of dead bacteria. For the first time, we propose a surface-initiated photoiniferter-mediated polymerization (SI-PIMP) strategy of constructing a "cleaning" zwitterionic outer layer on a polycationic bactericidal background layer to physically hinder the availability of polycationic moieties for mammalian cells in aqueous service. In dry conditions, the polycationic layer exerts the contact-active bactericidal property toward the adherent bacteria, as the zwitterionic layer collapses. In aqueous environment, the zwitterionic layer forms a hydration layer to significantly inhibit the attachment of planktonic bacteria and the accumulation of dead bacteria, while the polycationic layer kills bacteria occasionally deposited on the surface, thus preserving the antibacterial capability for a long period. More importantly, the zwitterionic hydrated layer protects the mammalian cells from toxicity induced by the bactericidal background layer, and therefore hierarchical antibacterial surfaces present much better biocompatibility than that of the naked cationic references. The dominant antibacterial mechanism of the hierarchical surfaces can switch from the bactericidal efficacy in dry storage to the bacteria repellent capability in aqueous service, showing great advantages in the infection-resistant applications.

Biological applications of lipoic acid-based polymers: an old material with new promise.

Lipoic acid (LA) is a versatile antioxidant that has been used in the treatment of various oxidation-reduction diseases over the past 70 years. Owing to its large five-membered ring tension, the dynamic disulfide bond of LA is highly active, enabling the formation of poly(lipoic acid) (PLA) via ring-opening polymerization (ROP). Herein, we first summarize disulfide-mediated ROP polymerization strategies, providing basic routes for designing and preparing PLA-based materials. PLA, as a biologically derived, low toxic, and easily modified material, possesses dynamic disulfide bonds and universal non-covalent carboxyl groups. We also shed light on the biomedical applications of PLA-based materials based on their biological and structural features and further divide recent works into six categories: antibacterial, anti-inflammation, anticancer, adhesive, flexible electronics, and 3D-printed tissue scaffolds. Finally, the challenges and future prospects associated with the biomedical applications of PLA are discussed.

Degradable Nanohydroxyapatite-Reinforced Superglue for Rapid Bone Fixation and Promoted Osteogenesis.

Bone glue with robust adhesion is crucial for treating complicated bone fractures, but it remains a formidable challenge to develop a "true" bone glue with high adhesion strength, degradability, bioactivity, and satisfactory operation time in clinical scenarios. Herein, inspired by the hydroxyapatite and collagen matrix composition of natural bone, we constructed a nanohydroxyapatite (nHAP) reinforced osteogenic backbone-degradable superglue (O-BDSG) by in situ radical ring-opening polymerization. nHAP significantly enhances adhesive cohesion by synergistically acting as noncovalent connectors between polymer chains and increasing the molecular weight of the polymer matrix. Moreover, nHAP endows the glue with bioactivity to promote osteogenesis. The as-prepared glue presented a 9.79 MPa flexural adhesion strength for bone, 4.7 times that without nHAP, and significantly surpassed commercial cyanoacrylate (0.64 MPa). O-BDSG exhibited degradability with 51% mass loss after 6 months of implantation. In vivo critical defect and tibia fracture models demonstrated the promoted osteogenesis of the O-BDSG, with a regenerated bone volume of 75% and mechanical function restoration to 94% of the native tibia after 8 weeks. The glue can be flexibly adapted to clinical scenarios with a curing time window of about 3 min. This work shows promising prospects for clinical application in orthopedic surgery and may inspire the design and development of bone adhesives.

A metal-organic framework-integrated composite for piezocatalysis-assisted tumour therapy: design, related mechanisms, and recent advances.

With the growing need for more effective tumour treatment, piezocatalytic therapy has emerged as a promising approach due to its distinctive capacities to generate ROS through stress induction and regulate the hypoxic state of the TME. MOF-based piezocatalysts not only possess the benefits of piezocatalysis but also exhibit several advantages associated with MOFs, such as tunable pore size, large specific surface area, and good biocompatibility. Therefore, they are expected to become a powerful promoter of piezocatalytic therapy. This review elaborates on the fundamental principles of piezocatalysis and summarises recent advances in the piezocatalytic therapy and combination therapies of tumours, generalising the strategies for constructing piezocatalytic systems based on MOFs. Finally, the challenges confronted and future opportunities for the design and application of piezocatalytic MOF anticancer systems have been discussed.

Metal-organic framework-based platforms for implantation applications: recent advances and challenges.

The development of minimally invasive technology has promoted the widespread use of implant interventional materials, which play an important role in alleviating patients' pain during and after surgery. Metal-organic frameworks (MOFs) and their related hybrids formed by bridging ligands and metal nodes via covalent bonds represent one of the smart platforms in implant interventional fields due to their large surface area, adjustable compositions and structures, biodegradability, etc. Significant progresses in the implantation application of MOF-based materials have been achieved recently, but these studies are still in the initial stage. This review highlights the recent advances of MOFs and their related hybrids in orthopedic implantation, cardio-vascular implantation, neural tissue engineering, and biochemical sensing. Each correction between the structural features of MOFs and their corresponding implanted works is highlighted. Finally, the confronting challenges and future perspectives in the implant interventional field are discussed.

Nanocomposite hyaluronic acid adhesive hydrogel with controllable drug release for bone regeneration.

Hyaluronic acid (HA) hydrogels have arisen as candidate materials to simulate the extracellular matrix and restore the functions of both cartilage and hard bones. However, integration of bone tissue adhesion and long-term osteogenic properties in one hydrogel is often ignored. Herein, a strategy to construct nanocomposite hydrogel with host tissue adhesive properties, enhanced mechanical strength, improved stability and osteogenic effects was developed. Simvastatin (SIM) was firstly incorporated into zeolitic imidazolate framework-8 (ZIF-8) and surface decoration with hydroxyapatite was realized to obtain SIM loaded and hydroxyapatite modified ZIF-8 particles (SP). As the inorganic strengthening component, SP could further cross-link the mixture of dopamine-hyaluronic acid (dHA) and tannic (TA) via coordination interaction to fabricate the hybrid adhesive hydrogel (dHA/TA/SP). Sufficient phenolic groups endowed dHA/TA/SP with excellent tissue adhesion and antibacterial properties, while incorporation of SP significantly improved the mechanical strength and stability of hydrogel. Further, due to the multiple protective effects of ZIF-8 and hydrogel, SIM was sustainably released from dHA/TA/SP. Together with the active Zn2+ and Ca2+, the expressions of ALP, OCN and RUNX2 were upregulated, and the mineralization was also promoted. With significant osteogenic effect in vitro and in vivo, this nanocomposite adhesive hydrogel holds great potential for bone defects repair.

Bionic double-crosslinked hydrogel of poly (γ-glutamic acid)/poly (N-(2-hydroxyethyl) acrylamide) with ultrafast gelling process and ultrahigh burst pressure for emergency rescue.

Injectable adhesive hydrogels combining rapid gelling with robust adhesion to wet tissues are highly required for fast hemostasis in surgical and major trauma scenarios. Inspired by the cross-linking mechanism of mussel adhesion proteins, we developed a bionic double-crosslinked (BDC) hydrogel of poly (γ-glutamic acid) (PGA)/poly (N-(2-hydroxyethyl) acrylamide) (PHEA) fabricated through a combination of photo-initiated radical polymerization and hydrogen bonding cross-linking. The BDC hydrogel exhibited an ultrafast gelling process within 1 s. Its maximum adhesion strength to wet porcine skin reached 254.5 kPa (9 times higher than that of cyanoacrylate (CA) glue) and could withstand an ultrahigh burst pressure of 626.4 mmHg (24 times higher than that of CA glue). Notably, the BDC hydrogel could stop bleeding within 10 s from a rat liver incision 10 mm long and 5 mm deep. The wound treated with the BDC hydrogel healed faster than the control groups, underlining the potential for emergency rescue and wound care scenarios.

Heparin-network-mediated long-lasting coatings on intravascular catheters for adaptive antithrombosis and antibacterial infection.

Bacteria-associated infections and thrombosis, particularly catheter-related bloodstream infections and catheter-related thrombosis, are life-threatening complications. Herein, we utilize a concise assembly of heparin sodium with organosilicon quaternary ammonium surfactant to fabricate a multifunctional coating complex. In contrast to conventional one-time coatings, the complex attaches to medical devices with arbitrary shapes and compositions through a facile dipping process and further forms robust coatings to treat catheter-related bloodstream infections and thrombosis simultaneously. Through their robustness and adaptively dissociation, coatings not only exhibit good stability under extreme conditions but also significantly reduce thrombus adhesion by 60%, and shows broad-spectrum antibacterial activity ( > 97%) in vitro and in vivo. Furthermore, an ex vivo rabbit model verifies that the coated catheter has the potential to prevent catheter-related bacteremia during implantation. This substrate-independent and portable long-lasting multifunctional coating can be employed to meet the increasing clinical demands for combating catheter-related bloodstream infections and thrombosis.

Optimization of Alkyl Side Chain Length in Polyimide for Gate Dielectrics to Achieve High Mobility and Outstanding Operational Stability in Organic Transistors.

Alkyl chain modification strategies in both organic semiconductors and inorganic dielectrics play a crucial role in improving the performance of organic thin-film transistors (OTFTs). Polyimide (PI) and its derivatives have received extensive attention as dielectrics for application in OTFTs because of flexibility, high-temperature resistance, and low cost. However, low-temperature solution processing PI-based gate dielectric for flexible OTFTs with high mobility, low operating voltage, and high operational stability remains an enormous challenge. Furthermore, even though di-n-decyldinaphtho[2,3-b:2',3'-f]thieno[3,2-b]thiophene (C10-DNTT) is known to have very high mobility as an air-stable and high-performance organic semiconductor, the C10-DNTT-based TFTs on the PI gate dielectrics still showed relatively low mobility. Here, inspired by alkyl side chain engineering, we design and synthesize a series of PI materials with different alkyl side chain lengths and systematically investigate the PI surface properties and the evolution of organic semiconductor morphology deposited on PI surfaces during the variation of alkyl side chain lengths. It is found that the alkyl side chain length has a critical influence on the PI surface properties, as well as the grain size and molecular orientation of semiconductors. Good field-effect characteristics are obtained with high mobilities (up to 1.05 and 5.22 cm2/Vs, which are some of the best values reported to date), relatively low operating voltage, hysteresis-free behavior, and high operational stability in OTFTs. These results suggest that the strategy of optimizing alkyl side-chain lengths opens up a new research avenue for tuning semiconductor growth to enable high mobility and outstanding operational stability of PI-based OTFTs.

Regulable Polyelectrolyte-Surfactant Complex for Antibacterial Biomedical Catheter Coating via a Readily Scalable Route.

Constructing multifunctional surfaces is one of the practical approaches to address catheter-related multiple complications but is generally time-consuming and substrate-dependent. Herein, a novel anti-adhesion, antibacterial, low friction, and robustness coating on medical catheters are developed via a universal and readily scalable method based on a regulable polyelectrolyte surfactant complex. The complex is rapidly assembled in one step by electrostatic and hydrophobic interactions between organosilicon quaternary ammonium surfactant (N+ Si ) and adjustable polyelectrolyte with cross-linkable, anti-adhesive, and anionic groups. The alcohol-soluble feature of the complex is conducive to the rapid formation of coatings on any medical device with arbitrary shapes via dip coating. Different from the conventional polyelectrolyte-surfactant complex coating, the regulated complex coating with nonleaching mode could be stable in harsh conditions (high concentration salt solution, organic reagents, etc.) because of the cross-linked structure while improving the biocompatibility and reducing the adhesion of various bacteria, proteins, and blood cells. The coated catheter exhibits good antibacterial infection in vitro and in vivo, owing to the synergistic effect of N+ Si and zwitterionic groups. Therefore, the rationally designed complex supplies a facile coating approach for the potential development in combating multiple complications of the medical catheter.

Brush Polymer Coatings with Hydrophilic Main-Chains for Improving Surface Antibacterial Properties.

Polymer coatings with improved surface antibacterial properties are of great importance for the application and development of implantable medical devices. Herein, we report the design, preparation, and antibacterial properties of a series of brush polymers (Dex-KEs) with hydrophilic dextran main-chains and mixed-charge polypeptide (KE) side-chains. Dex-KEs showed higher bactericidal activity and antifouling and antibiofilm properties than maleic acid modified dextran (Dex-Ma), KE, Dex-Ma/KE blend coatings, and brush polymer coatings with hydrophobic main-chains (AcDex-KEs). They also showed negligible in vitro cytotoxicity toward different mammalian cells and good in vivo biocompatibility. Dex-KE-coated implants exhibited potent in vivo resistance to bacterial infection before or after implantation.

Tunable backbone-degradable robust tissue adhesives via in situ radical ring-opening polymerization.

Adhesives with both robust adhesion and tunable degradability are clinically and ecologically vital, but their fabrication remains a formidable challenge. Here we propose an in situ radical ring-opening polymerization (rROP) strategy to design a backbone-degradable robust adhesive (BDRA) in physiological environment. The hydrophobic cyclic ketene acetal and hydrophilic acrylate monomer mixture of the BDRA precursor allows it to effectively wet and penetrate substrates, subsequently forming a deep covalently interpenetrating network with a degradable backbone via redox-initiated in situ rROP. The resulting BDRAs show good adhesion strength on diverse materials and tissues (e.g., wet bone >16 MPa, and porcine skin >150 kPa), higher than that of commercial cyanoacrylate superglue (~4 MPa and 56 kPa). Moreover, the BDRAs have enhanced tunable degradability, mechanical modulus (100 kPa-10 GPa) and setting time (seconds-hours), and have good biocompatibility in vitro and in vivo. This family of BDRAs expands the scope of medical adhesive applications and offers an easy and environmentally friendly approach for engineering.

Aquatic Diatoms-Inspired Universal Adhesive Coacervates Triggered by Water.

Adhesives with strong underwater adhesion performance are urgently needed in diverse areas. However, designing adhesives with long-term stability to diverse materials underwater in a facile way is challenging. Here, inspired by aquatic diatoms, a series of novel biomimetic universal adhesives is reported that shows tunable performance with robust and long-lasting stable underwater adhesion to various substrates, including wet biological tissues. The versatile and robust wet-contact adhesives are pre-polymerized by N-[tris(hydroxymethyl)methyl]acrylamide, n-butyl acrylate, and methylacrylic acid in dimethyl sulfoxide and spontaneously coacervated in water triggered by solvent exchange. The synergistic interaction between hydrogen bonding and hydrophobic interaction allows the hydrogels with instant and strong adhesion to various substrate surfaces. The slowly formed covalent bonds enhance cohesion and adhesion strength in hours. The spatial and timescale-dependent adhesion mechanism endows the adhesives with strong and long-lasting stable underwater adhesion to be coupled with fault-tolerant convenient surgical operations.