Antioxidant Silk Fibroin Composite Hydrogel for Rapid Healing of Diabetic Wound.

Wound healing is a complex process requiring multiple biological pathways and chemical responses to be activated and synchronized to recover tissue integrity. In normal physiological circumstances, the epidermal barrier restoration process through new tissue formation is highly efficient. However, increased production of reactive oxygen species (ROS), attack of pathogenic microorganisms, and high glucose level delay the normal healing process in diabetic patients. The successful treatment of diabetic wounds requires efficient strategies to control oxidative stress, promoting angiogenesis, re-epithelialization, and collagen deposition. In this study, a composite hydrogel for rapid wound healing in diabetic condition is developed by the amalgamation of hypolipidemic property of silk fibroin (SF), antioxidant property of melanin, and therapeutic effect of berberine. Studies have revealed that cross-linked mesoporous morphology of hydrogel matrix facilitates slow release of berberine to impart long-term therapeutic effects at wound site. The composite hydrogel formulation is biocompatible, stimulates effective migration of fibroblast cells, and control oxidative stress under in vitro conditions. The hydrogel served as scaffold for tissue re-epithelialization and promotes wound repair in diabetic type I Wistar rat model. This study demonstrates the ability of berberine- loaded SF-melanin composite hydrogel as a potential dressing formulation for wound healing in diabetic conditions.

Dual-Function Polymer-Silver Nanocomposites for Rapid Killing of Microbes and Inhibiting Biofilms.

Polymer-silver nanocomposites have emerged as an integral weapon to combat device-related infections. However, synthesis of the nanocomposites still remains a major challenge that often involves two-step process in which silver nanoparticles are synthesized ex situ. Additionally, polymers used in the nanocomposites are commonly not antimicrobial and biodegradable thus often lack bioactivity and biocompatibility. Herein we report highly active dual-function polymer-silver nanocomposites consisting of an inherently antimicrobial and biodegradable polymer in one-pot. A simple method of in situ reduction of a silver salt was employed to synthesize the silver nanoparticles (5-15 nm) from silver para-toluenesulfonate in which the intrinsically biodegradable and antimicrobial polymer N,N-dimethyl-N-hexadecyl ammonium chitin tosylate acted as reducing as well as stabilizing agent. The nanocomposite with the water-insoluble and organo-soluble polymer was simply painted onto surfaces via facile noncovalent immobilization. Notably, composite-coated surfaces inactivated both drug-sensitive and drug-resistant bacteria including pathogenic fungi at a much faster rate than polymer alone. The composites released active silver ions over an extended period of time and displayed remarkably long-lasting activity. In addition, surfaces coated with composites effectively inhibited both bacterial and fungal biofilm formation. Further, upon coating on catheter, the nanocomposites reduced methicillin-resistant Staphylococcus aureus (MRSA) burden both on catheter (>99.99% reduction) and in tissues surrounding the catheter (>99.999% reduction) in a mice model. These novel nanomaterials that showed negligible hemolysis toward human erythrocytes might be used as safe and effective antimicrobial coatings in biomedical device applications.

Dual Function Injectable Hydrogel for Controlled Release of Antibiotic and Local Antibacterial Therapy.

We present vancomycin-loaded dual-function injectable hydrogel that delivers antibiotic locally suitable for treatment of infections in avascular or necrotic tissues. The syringe-deliverable gels were developed using polydextran aldehyde and an inherently antibacterial polymer N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride along with vancomycin. The antibiotic was primarily encapsulated via reversible imine bonds formed between vancomycin and polydextran aldehyde in the hydrogel which allowed sustained release of vancomycin over an extended period of time in a pH-dependent manner. Being inherently antibacterial, the gels displayed excellent efficacy against bacteria due to dual mode of action (killing bacteria upon contact as well as by releasing antibiotics into surroundings). Upon subcutaneous implantation, the gel was shown to kill methicillin-resistant Staphylococcus aureus (>99.999%) when bacteria were introduced directly into the gel as well as at distal site from the gel in a mice model. These materials thus represent as novel noninvasive drug-delivery device suitable for local antibiotic therapy.

Biocompatible Injectable Hydrogel with Potent Wound Healing and Antibacterial Properties.

Two component injectable hydrogels that cross-link in situ have been used as noninvasive wound-filling devices, i.e., sealants. These materials carry a variety of functions at the wound sites, such as sealing leaks, ceasing unwanted bleeding, binding tissues together, and assisting in wound healing processes. However, commonly used sealants typically lack antibacterial properties. Since bacterial infection at the wound site is very common, bioadhesive materials with intrinsic antibacterial properties are urgently required. Herein, we report a biocompatible injectable hydrogel with inherent bioadhesive, antibacterial, and hemostatic capabilities suitable for wound sealing applications. The hydrogels were developed in situ from an antibacterial polymer, N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC), and a bioadhesive polymer, polydextran aldehyde. The gels were shown to be active against both Gram-positive and Gram-negative bacteria, including drug-resistant ones such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE), and ß-lactam-resistant Klebsiela pneumoniae. Mechanistic studies revealed that the gels killed bacteria upon contact by disrupting the membrane integrity of the pathogen. Importantly, the gels were shown to be efficacious in preventing sepsis in a cecum ligation and puncture (CLP) model in mice. While only 12.5% of animals survived in the case of mice with punctured cecam but with no gel on the punctured area (control), 62.5% mice survived when the adhesive gel was applied to the punctured area. Furthermore, the gels were also shown to be effective in facilitating wound healing in rats and ceasing bleeding from a damaged liver in mice. Notably, the gel showed negligible toxicity toward human red blood cells (only 2-3% hemolysis) and no inflammation to the surrounding tissue upon subcutaneous implantation in mice, thus proving it as a safe and effective antibacterial sealant.

In vivo antibacterial activity and pharmacological properties of the membrane-active glycopeptide antibiotic YV11455.

The membrane-active glycopeptide antibiotic YV11455 is a lipophilic cationic vancomycin analogue that demonstrates rapid and concentration-dependent killing of clinically relevant multidrug-resistant (MDR) Gram-positive bacteria in vitro. YV11455 was 2-fold and 54-270-fold more effective than vancomycin against clinical isolates of vancomycin-sensitive and vancomycin-resistant bacteria, respectively. In this study, the in vivo efficacy, pharmacodynamics, pharmacokinetics and acute toxicology of YV11455 were investigated. In vivo activity and pharmacodynamics were determined in the neutropenic mouse thigh infection model against meticillin-resistant Staphylococcus aureus (MRSA). YV11455 produced dose-dependent reductions in MRSA titres in thigh muscle. When administered intravenously, the 50% effective dose (ED(50)) for YV11455 against MRSA was found to be 3.3 mg/kg body weight, and titres were reduced by up to ca. 3log(10)CFU/g from pre-treatment values at a dosage of 12 mg/kg with single treatment. Single-dose pharmacokinetic studies demonstrated linear kinetics and a prolonged half-life, with an increase in drug exposure (area under the concentration-time curve) compared with vancomycin. The peak plasma concentration following an intravenous dose of 12 mg/kg was 543.5 µg/mL. Acute toxicology studies revealed that YV11455 did not cause any significant alterations in biochemical parameters or histological pictures related to major organs such as the liver and kidney at its pharmacodynamic endpoint (ED(3-log kill)). These findings collectively suggest that YV11455 could be used clinically for the treatment of infections caused by MDR Gram-positive bacteria.