A Glycosylated Cationic Block Poly(ß-peptide) Reverses Intrinsic Antibiotic Resistance in All ESKAPE Gram-Negative Bacteria.

Carbapenem-resistant Gram-negative bacteria (GNB) are heading the list of pathogens for which antibiotics are the most critically needed. Many antibiotics are either unable to penetrate the outer-membrane or are excluded by efflux mechanisms. Here, we report a cationic block ß-peptide (PAS8-b-PDM12) that reverses intrinsic antibiotic resistance in GNB by two distinct mechanisms of action. PAS8-b-PDM12 does not only compromise the integrity of the bacterial outer-membrane, it also deactivates efflux pump systems by dissipating the transmembrane electrochemical potential. As a result, PAS8-b-PDM12 sensitizes carbapenem- and colistin-resistant GNB to multiple antibiotics in vitro and in vivo. The ß-peptide allows the perfect alternation of cationic versus hydrophobic side chains, representing a significant improvement over previous antimicrobial α-peptides sensitizing agents. Together, our results indicate that it is technically possible for a single adjuvant to reverse innate antibiotic resistance in all pathogenic GNB of the ESKAPE group, including those resistant to last resort antibiotics.

Biomimetic zwitterionic copolymerized chitosan as an articular lubricant.

Restoration of the lubrication functions of articular cartilage is an effective treatment to alleviate the progression of osteoarthritis (OA). Herein, we fabricated chitosan-block-poly(sulfobetaine methacrylate) (CS-b-pSBMA) copolymer via a free radical polymerization of sulfobetaine methacrylate onto activated chitosan segment, structurally mimicking the lubricating biomolecules on cartilage. The successful copolymerization of CS-b-pSBMA was verified by Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and 1H nuclear magnetic resonance. Friction test confirmed that the CS-b-pSBMA copolymer could achieve an excellent lubrication effect on artificial joint materials such as Ti6Al4V alloy with a coefficient of friction as low as 0.008, and on OA-simulated cartilage, better than the conventional lubricant hyaluronic acid, and the adsorption effect of lubricant on cartilage surface was proved by a fluorescence labeling experiment. In addition, CS-b-pSBMA lubricant possessed an outstanding stability, which can withstand enzymatic degradation and even a long-term storage up to 4 weeks. In vitro studies showed that CS-b-pSBMA lubricant had a favorable antibacterial activity and good biocompatibility. In vivo studies confirmed that the CS-b-pSBMA lubricant was stable and could alleviate the degradation process of cartilage in OA mice. This biomimetic lubricant is a promising articular joint lubricant for the treatment of OA and cartilage restoration.

Amphiphilic nanofibrillated cellulose/polyurethane composites with antibacterial, antifouling and self-healing properties for potential catheter applications.

This study focuses on enhancing interventional medical devices, specifically catheters, using a novel composite material. Challenges like corrosion and contamination in vivo, often caused by body fluids' pH, bacteria, and proteins, lead to mechanical damage, bacterial colonization, and biofilm formation on devices like catheters. The objective of this study was to prepare a versatile composite (HFs) by designing polyurethanes (HPU) with an ionic chain extender (HIID) and blending them with amphiphilic nanofibrillated cellulose (Am-CNF). The composite leverages dynamic interactions such as hydrogen bonding and electrostatic forces, as evidenced by Molecular Mechanics (MM) calculations. The H4F0.75 composite exhibited exceptional properties: 99 % length recovery post 600 stretching cycles at 100 % strain, rapid self-healing in artificial urine, high bactericidal activity, and excellent cell viability. Moreover, mechanical aging tests and UV-vis spectral analysis confirmed the material's durability and safety. These findings suggest that the HFs composite holds significant promise for improving catheters' performance in medical applications.

A lubricant and adhesive hydrogel cross-linked from hyaluronic acid and chitosan for articular cartilage regeneration.

Trauma-induced articular cartilage damages are common in clinical practice. Hydrogels have been used to fill the cartilage defects and act as extracellular matrices for cell migration and tissue regeneration. Lubrication and stability of the filler materials are essential to achieve a satisfying healing effect in cartilage regeneration. However, conventional hydrogels failed to provide a lubricous effect, or could not anchor to the wound to maintain a stable curing effect. Herein, we fabricated dually cross-linked hydrogels using oxidized hyaluronic acid (OHA) and N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC) methacrylate (HTCCMA). The OHA/HTCCMA hydrogels, which were dynamically cross-linked and then covalently cross-linked by photo-irradiation, showed appropriate rheological properties and self-healing capability. The hydrogels exhibited moderate and stable tissue adhesion property due to formation of dynamic covalent bonds with the cartilage surface. The coefficient of friction values were 0.065 and 0.078 for the dynamically cross-linked and double-cross-linked hydrogels, respectively, demonstrating superior lubrication. In vitro studies showed that the hydrogels had good antibacterial ability and promoted cell proliferation. In vivo studies confirmed that the hydrogels were biocompatible and biodegradable, and exhibited a robust regenerating ability for articular cartilage. This lubricant-adhesive hydrogel is expected to be promising for the treatment of joint injuries as well as regeneration.

Tannic acid-reinforced zwitterionic hydrogels with multi-functionalities for diabetic wound treatment.

Diabetic wounds remain one of the most prevalent hard-to-heal wounds in the clinic. The causative factors impeding the wound healing process include not only the elevated oxidative stress and bacterial infections but also the high and repetitive plantar stress (including compressive pressure and shear stress). Conventional hydrogel dressings are mechanically weak and fragile, limiting their applications in the high stress-loading conditions of diabetic foot ulcers. As such, mechanically tough hydrogel dressings with appropriate bioactivities are highly desirable for diabetic wound treatment. In this study, a mechanically reinforced hydrogel with multiple biofunctionalities was developed via a facile and straightforward strategy of incorporation of tannic acid (TA) in zwitterionic poly(sulfobetaine methacrylate) (polySBMA) hydrogel. The polySBMA hydrogel reinforced by TA showed excellent mechanical property, with the tensile stress and compressive stress up to 93.7 kPa and 18.4 MPa, respectively, and it could resist cyclic compressive stress at ∼200 kPa (maximum in-shoe plantar pressure) for up to 3500 cycles. The TA-reinforced zwitterionic hydrogel exhibited strong adhesion to skin tissue (20.2 kPa), which was expected to reduce the shear stress on the foot. The plantar pressure on the foot was significantly reduced by the application of the resilient hydrogel. Attributed to the antioxidant and antibacterial properties of TA, the hydrogel showed rapid radical scavenging capability and strong bactericidal efficacy against Gram-positive and Gram-negative bacteria. In vitro and in vivo studies confirmed that the hydrogel has good cytocompatibility and negligible skin irritation, and promoted healing of diabetic wounds in mice. Such tough and effective hydrogel with a straightforward preparation strategy holds great promise as wound dressings for diabetic wound treatment.

Solvent-Free Fabrication of Self-Regenerating Antibacterial Surfaces Resisting Biofilm Formation.

Biofilm formation on indwelling medical devices is a major cause of hospital-acquired infections. Monofunctional antibacterial surfaces have been developed to resist the formation of biofilms by killing bacteria on contact, but the adsorption of killed bacterial cells and debris gradually undermines the function of these surfaces. Here, we report a facile approach to produce an antibacterial surface that can regenerate its function after contamination. The self-regenerating surface was achieved by sequential deposition of alternating antibacterial and biodegradable layers of coating using a solvent-free initiated chemical vapor deposition method. As the top antibacterial layer gradually loses its killing ability due to the accumulation of debris, the underlying biodegradable layer degrades, shedding off the top surface layers and exposing another fresh antibacterial surface. Urinary catheters coated with monofunctional and self-regenerating antibacterial coatings both showed more than 99% bacterial killing ability at the initial antibacterial test, but the monofunctional surface lost its killing ability after continued exposure to concentrated bacterial solution, whereas the self-regenerating surfaces regained strong bacterial killing ability after prolonged exposure. Employing poly(methacrylic anhydride) and its copolymers with varied composition as the degrading layer, the degradation kinetics can be well-tailored and the self-regeneration duration spanned from minutes to days. The designed self-regenerating antibacterial surfaces could provide an effective approach to resist biofilm formation and extend the service life of indwelling medical devices.

Various administration forms of decellularized amniotic membrane extract towards improving corneal repair.

Amniotic membrane (AM) transplantation is often used as a treatment for corneal repair, but AM is prone to dissolving and shedding after surgery; multiple transplants will cause pain and financial burden. In this work, human amniotic membrane was firstly decellularized to obtain an AM extracellular matrix (dAM). This dAM was homogenized and extracted to obtain the dAM extract (simplified as dAME). Different forms of administration for corneal injury were performed as liquid drops (diluted dAME), in situ gels (using temperature-dependent Poloxamer 407 as the matrix), and tablets (poly(vinyl alcohol) as the matrix). The cytocompatibility of dAME was evaluated using corneal epithelial cells, corneal stromal cells and fibroblasts as cell models. The results showed that dAME is biocompatible to all these cells. Cells exhibited normal morphology and growth state at a dAME concentration of up to 160 µg mL-1. In vivo, dAME exhibited increased wound healing efficiency in severe corneal injury, being characterized with a shorter healing time for epithelium and a faster recovery for stromal opacity and thickness, compared with those of the control eyes. Different forms of administration have different effects on corneal repair; among them, in situ gels achieved the best therapeutic efficiency. Their biological mechanism was detected via quantitative real-time polymerase chain reaction (qRT-PCR) technology. It was confirmed that dAME plays important roles in promoting the mRNA expression of leucine-rich and immunoglobulin-like domains 1 (LRIG1) and in inhibiting the mRNA of transforming growth factor-ß1 (TGF-ß1).

Development of Poloxamer Hydrogels Containing Antibacterial Guanidine-Based Polymers for Healing of Full-Thickness Skin Wound.

A series of hydrogels containing guanidine-based polymers using a poloxamer as the matrix were prepared to provide novel wound dressings with antibacterial and repairing-promotion properties for skin wounds. Herein, we developed a series of antibacterial hydrogels, the cationic guanidine-based polymer polyhexamethylene guanidine hydrochloride (PHMG) with poloxamer aqueous solution (12%, w/w) simplified as PHMGP, chitosan (CS)-cross-linked PHMG (referred to as PHMC) with poloxamer aqueous solution simplified as PHMCP, and hyaluronic acid (HA)-modified PHMG (referred to as PHMH) with poloxamer aqueous solution simplified as PHMHP, for enhancing full-thickness skin wound healing. The characterizations, antimicrobial activity, cytotoxicity, and in vivo full-thickness wound-healing capability of these hydrogels were analyzed and evaluated. The results show that though PHMGP possesses great bactericide properties, its cytotoxicity is too strong to support skin regeneration. However, after modified with CS or HA, PHMCP and PHMHP showed good biocompatibility and antimicrobial properties against Gram-positive and Gram-negative bacteria that are commonly present in injured skin. Both PHMCP and PHMHP hydrogels exhibited upgraded wound-healing efficiency in full-thickness skin defects, characterized by a shorter wound closure time, faster re-regeneration, and the earlier formation of skin appendages, compared with those of control or pure poloxamer treatments. Their biological mechanism was detected. Both PHMCP and PHMHP can regulate the related biofactors during the skin repair process such as interleukin-1ß (IL-1ß), interleukin-6 (IL-6), transforming growth factor beta-1(TGF-ß1), alpha-smooth muscle actin (α-SMA), and vascular endothelial growth factor, to promote wound healing with less serious scarring. In short, hydrogels with excellent capabilities to inhibit microorganism infection and promote wound healing were developed, which will shed light on designing and producing wound dressings with promising applications in future.

Chitosan-Based Functional Materials for Skin Wound Repair: Mechanisms and Applications.

Skin wounds not only cause physical pain for patients but also are an economic burden for society. It is necessary to seek out an efficient approach to promote skin repair. Hydrogels are considered effective wound dressings. They possess many unique properties like biocompatibility, biodegradability, high water uptake and retention etc., so that they are promising candidate materials for wound healing. Chitosan is a polymeric biomaterial obtained by the deacetylation of chitin. With the properties of easy acquisition, antibacterial and hemostatic activity, and the ability to promote skin regeneration, hydrogel-like functional wound dressings (represented by chitosan and its derivatives) have received extensive attentions for their effectiveness and mechanisms in promoting skin wound repair. In this review, we extensively discussed the mechanisms with which chitosan-based functional materials promote hemostasis, anti-inflammation, proliferation of granulation in wound repair. We also provided the latest information about the applications of such materials in wound treatment. In addition, we summarized the methods to enhance the advantages and maintain the intrinsic nature of chitosan via incorporating other chemical components, active biomolecules and other substances into the hydrogels.

Pranoprofen Nanoparticles With Poly(L-Lactide)-b-Poly(Ethylene Glycol)-b-Poly(L-Lactide) as the Matrix Toward Improving Ocular Anti-inflammation.

Nanotechnology using biodegradable polymer carriers with good biocompatibility and bioabsorbability has been studied and applied extensively in drug delivery systems and biomedical engineering. In this work, the triblocked oligomer poly(L-lactide)-b-poly(ethylene glycol)-b-poly(L-lactide) (PLEL) with the molecular weight of 2.08 KDa was first synthesized. Its chemistry was characterized by hydrogen nuclear magnetic resonance (1H-NMR) spectrum and Fourier transform infrared (FTIR) spectroscopy. Subsequently, the nanoparticles (NPs) of PLEL and pranoprofen (PF)-loaded PLEL were prepared with the average particle size of (151.7 ± 5.87) nm using the method of emulsion solvent evaporation. The formula and drug releasing profile were characterized by a transmission electron microscope (TEM), dynamic light scattering (DLS), and ultraviolet spectrophotometer (US). In vitro cytotoxicity assays and in vivo ophthalmic tests were performed to measure the safety and efficacy of the formulations. The results showed that PF NPs relieved the cytotoxicity of pure PF and eliminated ophthalmic irritation. The drug encapsulated in the nanoparticles displayed long-lasting release and good anti-inflammation efficiency in animal eyes. Therefore, we concluded that the present formula (PF NPs) could provide sustained drug release with good treatment effect on eye inflammation, and is promising for its use in ophthalmology in the future.

The Mechanisms and the Applications of Antibacterial Polymers in Surface Modification on Medical Devices.

Medical device contamination caused by microbial pathogens such as bacteria and fungi has posed a severe threat to the patients' health in hospitals. Due to the increasing resistance of pathogens to antibiotics, the efficacy of traditional antibiotics treatment is gradually decreasing for the infection treatment. Therefore, it is urgent to develop new antibacterial drugs to meet clinical or civilian needs. Antibacterial polymers have attracted the interests of researchers due to their unique bactericidal mechanism and excellent antibacterial effect. This article reviews the mechanism and advantages of antimicrobial polymers and the consideration for their translation. Their applications and advances in medical device surface coating were also reviewed. The information will provide a valuable reference to design and develop antibacterial devices that are resistant to pathogenic infections.

Solvent-Free Graft-From Polymerization of Polyvinylpyrrolidone Imparting Ultralow Bacterial Fouling and Improved Biocompatibility.

Polymer grafting has been a powerful tool in the surface modification of biomaterials. Traditional solvent-based grafting, however, often requires laborious procedures taken under harsh conditions, which seriously hinders its practical applications. Here, we report a facile solvent-free graft-from method that is able to achieve a superior surface functionality as compared to most reported results from traditional solvent-based grafting. The grafting was proceeded by conformally coating a cross-linked polyvinylpyrrolidone (PVP) prime layer in the vacuum, immediately followed by in situ grafting of PVP homopolymer chains from the propagating sites on the coating surface. The resultant coating exhibited enriched surface pyrrolidone content compared to the single-layer cross-linked counterpart and a water contact angle of 22°, lower than most reported PVP-grafted surfaces. Medical catheters grafted with PVP achieved a more than 99.9% bacterial antifouling enhancement compared to the pristine catheter, and significantly improved biocompatibility during a 4 week in vivo test in mice. The achieved surface functionality is attributed to the synergistic effect from the functional groups distributed both on the grafted chains and on the cross-linked primer. The effectiveness and simplicity of the vapor grafting method thus suggest a promising surface modification route for biomaterials and beyond.