Polymyxin B Conjugates with Bio-Inspired Synthetic Polymers of Different Nature.

The emergence and growth of bacterial resistance to antibiotics poses an enormous threat to humanity in the future. In this regard, the discovery of new antibiotics and the improvement of existing ones is a priority task. In this study, we proposed the synthesis of new polymeric conjugates of polymyxin B, which is a clinically approved but limited-use peptide antibiotic. In particular, three carboxylate-bearing polymers and one synthetic glycopolymer were selected for conjugation with polymyxin B (PMX B), namely, poly(α,L-glutamic acid) (PGlu), copolymer of L-glutamic acid and L-phenylalanine (P(Glu-co-Phe)), copolymer of N-vinyl succinamic acid and N-vinylsuccinimide (P(VSAA-co-VSI)), and poly(2-deoxy-2-methacrylamido-D-glucose) (PMAG). Unlike PGlu and PMAG, P(Glu-co-Phe) and P(VSAA-co-VSI) are amphiphilic and form nanoparticles in aqueous media. A number of conjugates with different polymyxin B loading were synthesized and characterized. In addition, the complex conjugates of PGLu or PMAG with polymyxin B and deferoxamine (siderophore) were obtained. A release of PMX B from Schiff base and amide-linked polymer conjugates was studied in model buffer media with pH 7.4 and 5.8. In both cases, a more pronounced release was observed under slightly acidic conditions. The cytotoxicity of free polymers and PMX B as well as their conjugates was examined in human embryonic kidney cells (HEK 293T cell line). All conjugates demonstrated reduced cytotoxicity compared to the free antibiotic. Finally, the antimicrobial efficacy of the conjugates against Pseudomonas aeruginosa was determined and compared. The lowest values of minimum inhibitory concentrations (MIC) were observed for polymyxin B and polymyxin B/deferoxamine conjugated with PMAG. Among the polymers tested, PMAG appears to be the most promising carrier for delivery of PMX B in conjugated form due to the good preservation of the antimicrobial properties of PMX B and the ability of controlled drug release.

Evaluation of hyaluronic acid nanoparticle embedded chitosan-gelatin hydrogels for antibiotic release.

The development of chitosan-gelatin (CS-G) hydrogels embedded with ampicillin-loaded hyaluronic acid nanoparticles (HA-NPs) for wound dressing is proposed. It was aimed to provide controlled ampicillin delivery by incorporation of HA-NPs into biocompatible CS-G hydrogel structure. According to in vitro ampicillin release studies, 55% of ampicillin was released from CS-G/HA-NPs hydrogels after 5 days. Antibacterial performance of CS-G/HA-NPs hydrogels was proven with agar disc diffusion test. For cytotoxicity assay, fibroblast cell viability increased in CS-G/HA-NPs hydrogels compared with CS-G group after 24 hr incubation. Consequently, the potential ability of CS-G/HA-NPs hydrogels as a controlled drug delivery system has been verified.

Current Options and Emerging Biomaterials for Periprosthetic Joint Infection.

PURPOSE OF REVIEW: Infection in the setting of total joint arthroplasty, referred to as periprosthetic joint infection (PJI), is a devastating complication requiring prolonged and costly treatment. The unique environment around an artificial joint and ability of surrounding tissues to sequester bacteria collectively make prevention, diagnosis, and treatment of this condition challenging. In light of the unique pathogenesis of PJI, this review explores the limitations of contemporary treatments and discusses novel treatment options. RECENT FINDINGS: Recent advancements in local antibiotic delivery platforms for preventing and treating PJI include titanium nanotube arrays, synthetic polymers, resorbable hydrogels, and cyclodextrin-based drug delivery options. In particular, cyclodextrins have facilitated great advancements in other clinical disorders and have demonstrated early promise as a future option in the arena of PJI. Novel treatment modalities for PJI optimize the implant surfaces to prevent bacterial biofilm formation or provide prolonged intra-articular antibiotic dosing to eradicate bacteria.

Targeted antibiotic delivery using low temperature-sensitive liposomes and magnetic resonance-guided high-intensity focused ultrasound hyperthermia.

Chronic non-healing wound infections require long duration antibiotic therapy, and are associated with significant morbidity and health-care costs. Novel approaches for efficient, readily-translatable targeted and localised antimicrobial delivery are needed. The objectives of this study were to 1) develop low temperature-sensitive liposomes (LTSLs) containing an antimicrobial agent (ciprofloxacin) for induced release at mild hyperthermia (∼42 °C), 2) characterise in vitro ciprofloxacin release, and efficacy against Staphylococcus aureus plankton and biofilms, and 3) determine the feasibility of localised ciprofloxacin delivery in combination with MR-HIFU hyperthermia in a rat model. LTSLs were loaded actively with ciprofloxacin and their efficacy was determined using a disc diffusion method, MBEC biofilm device, and scanning electron microscopy (SEM). Ciprofloxacin release from LTSLs was assessed in a physiological buffer by fluorescence spectroscopy, and in vivo in a rat model using MR-HIFU. Results indicated that < 5% ciprofloxacin was released from the LTSL at body temperature (37 °C), while >95% was released at 42 °C. Precise hyperthermia exposures in the thigh of rats using MR-HIFU during intravenous (i.v.) administration of the LTSLs resulted in a four fold greater local concentration of ciprofloxacin compared to controls (free ciprofloxacin + MR-HIFU or LTSL alone). The biodistribution of ciprofloxacin in unheated tissues was fairly similar between treatment groups. Triggered release at 42 °C from LTSL achieved significantly greater S. aureus killing and induced membrane deformation and changes in biofilm matrix compared to free ciprofloxacin or LTSL at 37 °C. This technique has potential as a method to deliver high concentration antimicrobials to chronic wounds.

Functionalized Antimicrobial Composite Thin Films Printing for Stainless Steel Implant Coatings.

In this work we try to address the large interest existing nowadays in the better understanding of the interaction between microbial biofilms and metallic implants. Our aimed was to identify a new preventive strategy to control drug release, biofilm formation and contamination of medical devices with microbes. The transfer and printing of novel bioactive glass-polymer-antibiotic composites by Matrix-Assisted Pulsed Laser Evaporation into uniform thin films onto 316 L stainless steel substrates of the type used in implants are reported. The targets were prepared by freezing in liquid nitrogen mixtures containing polymer and antibiotic reinforced with bioglass powder. The cryogenic targets were submitted to multipulse evaporation by irradiation with an UV KrF* (λ = 248 nm, τFWHM ≤ 25 ns) excimer laser source. The prepared structures were analyzed by infrared spectroscopy, scanning electron microscopy, energy dispersive X-ray spectroscopy and profilometry, before and after immersion in physiological fluids. The bioactivity and the release of the antibiotic have been evaluated. We showed that the incorporated antibiotic underwent a gradually dissolution in physiological fluids thus supporting a high local treatment efficiency. Electrochemical measurements including linear sweep voltammetry and impedance spectroscopy studies were carried out to investigate the corrosion resistance of the coatings in physiological environments. The in vitro biocompatibility assay using the MG63 mammalian cell line revealed that the obtained nanostructured composite films are non-cytotoxic. The antimicrobial effect of the coatings was tested against Staphylococcus aureus and Escherichia coli strains, usually present in implant-associated infections. An anti-biofilm activity was evidenced, stronger against E. coli than the S. aureus strain. The results proved that the applied method allows for the fabrication of implantable biomaterials which shield metal ion release and possess increased biocompatibility and resistance to microbial colonization and biofilm growth.

Features of Changes in the Structure and Properties of a Porous Polymer Material with Antibacterial Activity during Biodegradation in an In Vitro Model.

Hybrid porous polymers based on poly-EGDMA and polylactide containing vancomycin, the concentration of which in the polymer varied by two orders of magnitude, were synthesized. The processes of polymer biodegradation and vancomycin release were studied in the following model media: phosphate-buffered saline (PBS), trypsin-Versene solution, and trypsin-PBS solution. The maximum antibiotic release was recorded during the first 3 h of extraction. The duration of antibiotic escape from the polymer samples in trypsin-containing media varied from 3 to 22 days, depending on the antibiotic content of the polymer. Keeping samples of the hybrid polymer in trypsin-containing model media resulted in acidification of the solutions-after 45 days, up to a pH of 1.84 in the trypsin-Versene solution and up to pH 1.65 in the trypsin-PBS solution. Here, the time dependences of the vancomycin release from the polymer into the medium and the decrease in pH of the medium correlated. These data are also consistent with the results of a study of the dynamics of sample weight loss during extraction in the examined model media. However, while the polymer porosity increased from ~53 to ~60% the pore size changed insignificantly, over only 10 µm. The polymer samples were characterized by their antibacterial activity against Staphylococcus aureus, and this activity persisted for up to 21 days during biodegradation of the material, regardless of the medium type used in model. Surface-dependent human cells (dermal fibroblasts) adhere well, spread out, and maintain high viability on samples of the functionalized hybrid polymer, thus demonstrating its biocompatibility in vitro.

Composite Bone Cements with Enhanced Drug Elution.

Antibiotic-loaded bone cement (ALBC) has become an indispensable material in orthopedic surgery in recent decades, owing to the possibility of drugs delivery to the surgical site. It is applied for both infection prophylaxis (e.g., in primary joint arthroplasty) and infection treatment (e.g., in periprosthetic infection). However, the introduction of antibiotic to the polymer matrix diminishes the mechanical strength of the latter. Moreover, the majority of the loaded antibiotic remains embedded in polymer and does not participate in drug elution. Incorporation of the various additives to ALBC can help to overcome these issues. In this paper, four different natural micro/nanoscale materials (halloysite, nanocrystalline cellulose, micro- and nanofibrillated cellulose) were tested as additives to commercial Simplex P bone cement preloaded with vancomycin. The influence of all four materials on the polymerization process was comprehensively studied, including the investigation of the maximum temperature of polymerization, setting time, and monomer leaching. The introduction of the natural additives led to a considerable enhancement of drug elution and microhardness in the composite bone cements compared to ALBC. The best combination of the polymerization rate, monomer leaching, antibiotic release, and microhardness was observed for the sample containing nanofibrillated cellulose (NFC).

Injectable metronidazole-eluting gelatin-alginate hydrogels for local treatment of periodontitis.

Infection of the periodontal pocket presents two major challenges for drug delivery: administration into the periodontal pocket and a high fluid clearance rate in the pocket. The current study aimed to develop and study a novel hydrogel system for delivery of the antibiotic drug metronidazole directly into the periodontal pocket via injection followed by in situ gelation. The natural polymers gelatin and alginate served as basic materials, and their crosslinking using a carbodiimide resulted in a dual hydrogel network. The study focused on the effects of the hydrogel's formulation parameters on the drug release profile and the hydrogel's physical and mechanical properties. A cell viability test was conducted on human fibroblasts. The metronidazole-loaded hydrogels demonstrated a decreasing release rate with time, where most of the drug eluted within 24 h. These hydrogels exhibited fibroblast viability of at least 75% after 24 and 48 h, indicating that they are highly biocompatible. Although the alginate concentration used in this study was relatively low, it had a strong effect on the physical as well as the mechanical properties of the hydrogel. An increase in the alginate concentration increased the crosslinking rate and enabled enhanced entanglement of the 3D structure, resulting in a decrease in the gelation time (less than 10 s) and swelling degree, which are both desired for the studied periodontal application. Increasing the gelatin concentration without changing the crosslinker concentration resulted in significant changes in the physical properties and slight changes in the mechanical properties. Metronidazole incorporation slightly decreased the hydrophilicity of the hydrogel and therefore also its viscosity, and affected the sealing ability and the tensile and compression moduli. The developed hydrogels exhibited controllable mechanical and physical properties, can target a wide range of conditions, and are therefore of high significance in the field of periodontal treatment.

Near-infrared light-responsive and antibacterial injectable hydrogels with antioxidant activity based on a Dopamine-functionalized Gellan Gum for wound healing.

The development of wound dressings with combined antioxidant, antibacterial and tissue adhesion functions has been a difficult medical task for the treatment of wound infections. We synthetized a dopamine and PEG functionalized Gellan Gum (GG) to produce an injectable hydrogel with radical scavenging activity having both specific and aspecific antibiotic/antimicrobial properties. Using starting GG with different molecular weights, we obtained two derivatives that have been used to prepare the gel precursor dispersion, that undergoes gelation in the presence of colistin and dried microparticles (MPs) functionalized on the surface with polydopamine (pDA). Both were used to dope the hydrogel, increase the radical scavenger activity and impart near-infrared light (NIR) responsiveness. Indeed, with an irradiation of 810 nm, the incorporated microparticles exhibit photothermal transformation properties and improve the release of antibiotics on demand. The combination of photothermal and antibiotic therapy with synergistic antibacterial action acts on Pseudomonas aeruginosa and leads to a bactericidal effect in a few hours, while on Staphylococcus aureus there is an effect of inhibition of growth over time due only to the hyperthermic effect. We believe this study provides a promising method for fabricating a multifunctional injectable hydrogel for the potential treatment of infected skin wounds.

Stimuli-sensitive drug delivery systems for site-specific antibiotic release.

Site-specific delivery of antibiotics has always been a high-priority area in pharmaceutical research. Conventionally used antibiotics suffer several limitations, such as low accumulation and penetration in diseased cells/tissues, limited bioavailability of drugs, drug resistance, and off-target toxicity. To overcome these limitations, several strategies have been exploited for delivering antibiotics to the site of infection, such as the use of stimuli-responsive antibiotic delivery systems, which can release antibiotics in a controlled and timely fashion. These stimuli can either be exogenous (light, magnetism, ultrasound, and electrical) or endogenous (pH, redox reactions, and enzymatic). In this review, we present a summary of recent developments in the field of stimuli-based targeted drug delivery systems for the site-specific release of antibiotics.

Ciprofloxacin releasing gellan gum/polydopamine based hydrogels with near infrared activated photothermal properties.

In this work, with the aim to obtain a wound dressing hydrogel, an amine derivative of gellan gum was crosslinked in the presence of 4arm-polyethylenglycole-vinylsulfone. Through this easy and reproducible chemical procedure, a hydrogel with advanced elastic properties and hydrolytic resistance under physiological conditions was obtained. The incorporation of different quantities of polydopamine in the gelling solutions allows to obtain different hydrogels with marked photothermal properties when irradiated with a laser in the near infrared at 810 nm. The organic nanoparticles, reacting with the amino groups of the polysaccharide derivative, contribute to increase the storage moduli of the hydrogels. Ciprofloxacin was loaded into the hydrogel with higher amount of polydopamine and drug delivery experiments were performed to investigate the effect of irradiation on the antibiotic release profile. Antimicrobial studies, evaluated against S. aureus and P. aeruginosa, revealed that generated hyperthermia exerts a direct inhibition on the pathogens growth and, in the case of S. aureus, adjuvates the ciprofloxacin antimicrobial effect.

In vitro characterization of novel multidrug-eluting soy protein wound dressings.

Polymers derived from natural sources are of interest in the scientific and medical communities, especially soy protein which exhibits low immunogenicity and good mechanical properties, and supports cell proliferation. Soy protein is cost-effective compared to other natural polymers and is attractive also due to its non-animal origin and relatively long storage stability. In the current study, hybrid film structures were developed and studied as a novel wound dressing platform with controlled release of three bioactive agents. The dense top layer is designed to provide mechanical support, control the water vapor permeability and to elute the antibiotic drug cloxacillin and the analgesic drug bupivacaine to the wound site. The porous sub-layer is designed to absorb the wound exudates and release the hemostatic agent tranexamic acid for bleeding control. The results show that the formulation parameters, i.e. crosslinker and plasticizer concentrations, affected the mechanical properties of the wound dressings as well as relevant physical properties (water vapor transmission rate and swelling kinetics), but had almost no effect on the drug-release profiles. While the antibiotic drug and the analgesic drug were released within several hours, the hemostatic agent was released within several minutes, according to the well designed hybrid structure. In conclusion, our novel soy protein hybrid wound dressings are biocompatible, can deliver various drugs simultaneously in a controlled fashion for each drug individually, and can be adjusted to suit various types of wounds by altering their properties through formulation effects.

Ag-Doped and Antibiotic-Loaded Hexagonal Boron Nitride Nanoparticles as Promising Carriers to Fight Different Pathogens.

Utilization of antibacterial components-conjugated nanoparticles (NPs) is emerging as an attractive strategy for combating various pathogens. Herein, we demonstrate that Ag/BN NPs and antibiotic-loaded BN and Ag/BN nanoconjugates are promising carriers to fight bacterial and fungal infections. Extensive biological tests included two types of Gram-positive methicillin-resistant Staphylococcus aureus strains (B8469 and MW2), two types of Gram-negative Pseudomonas aeruginosa strains (ATCC27853 and B1307/17), and 47 types of Escherichia coli strains (including 41 multidrug-resistant ones), as well as five types of fungal cultures: Candida albicans (candidiasis-thrush) ATCC90028 and ATCC24433, Candida parapsilosis ATCC90018, Candida auris CBS109113, and Neurospora crassa wt. We have demonstrated that, even within a single genus Escherichia, there are many hospital E. coli strains with multi-drug resistance to different antibiotics. Gentamicin-loaded BN NPs have high bactericidal activity against S. aureus, P. aeruginosa, and 38 types of the E. coli strains. For the rest of the tested E. coli strains, the Ag nanoparticle-containing nanohybrids have shown superior bactericidal efficiency. The Ag/BN nanohybrids and amphotericin B-loaded BN and Ag/BN NPs also reveal high fungicidal activity against C. albicans, C. auris, C. parapsilosis, and N. crassa cells. In addition, based on the density functional theory calculations, the nature of antibiotic-nanoparticle interaction, the sorption capacity of the BN and Ag/BN nanohybrids for gentamicin and amphotericin B, and the most energetically favorable positions of the drug molecules relative to the carrier surface, which lead to lowest binding energies, have been determined. The obtained results clearly show high therapeutic potential of the antibiotic-loaded Ag/BN nanocarriers providing a broad bactericidal and fungicidal protection against all of the studied pathogens.

Drug Release from Thermo-Responsive Polymer Brush Coatings to Control Bacterial Colonization and Biofilm Growth on Titanium Implants.

Despite decades of biomedical advances, the colonization of implant devices with bacterial biofilms is still a leading cause of implant failure. Clearly, new strategies and materials that suppress both initial and later stage bacterial colonization are required in this context. Ideal would be the implementation of a bactericidal functionality in the implants that is temporally and spatially triggered in an autonomous fashion at the infection site. Herein, the fabrication and validation of functional titanium-based implants with triggered antibiotic release function afforded via an intelligent polymer coating is reported. In particular, thermo-responsive poly(di(ethylene glycol) methyl ether methacrylate) (PDEGMA) brushes on titanium implants synthesized via a surface-initiated atom transfer radical polymerization with activators regenerated through the electron transfer technique (ARGET ATRP) allows for a controlled and thermally triggered release of the antibiotic levofloxacin at the wound site. Antibiotic loaded brushes are investigated as a function of thickness, loading capacity for antibiotics, and temperature. At temperatures of the infection site >37 °C the lower critical solution temperature behavior of the brushes afforded the triggered release. Hence, in addition to the known antifouling effects, the PDEGMA coating ensured enhanced bactericidal effects, as demonstrated in initial in vivo tests with rodents infected with Staphylococcus aureus.

Rational collaborative ablation of bacterial biofilms ignited by physical cavitation and concurrent deep antibiotic release.

Bacteria biofilm has extracellular polymeric substances to protect bacteria from external threats, which is a stubborn problem for human health. Herein, a kind of gasifiable nanodroplet is fabricated to ablate Staphylococcus aureus (S. aureus) biofilm. Upon NIR pulsed laser irradiation, the nanodroplets can gasify to generate destructive gas shockwave, which further potentiates initial acoustic cavitation effect, thus synergistically disrupting the protective biofilm and killing resident bacteria. More importantly, the gasification can further promote antibiotic release in deep biofilm for residual bacteria eradication. The nanodroplets not only exhibit deep biofilm penetration capacity and high potency to ablate biofilms, but also good biocompatibility without detectable side effects. In vivo mouse implant model indicates that the nanodroplets can accumulate at the S. aureus infected implant sites. Upon pulsed laser treatment, the nanodroplets efficiently eradicate bacteria biofilm in implanted catheter by synergistic contribution of gas shockwave-enhanced cavitation and deep antibiotic release. Current phase changeable nanodroplets with synergistic physical and chemical therapeutic modalities are promising to combat complex bacterial biofilms with drug resistance, which provides an alternative visual angle for biofilm inhibition in biomedicine.

Antimicrobial activity and biocompatibility of slow-release hyaluronic acid-antibiotic conjugated particles.

Here, the aim was to design and use a long-lasting antibiotic release system for prevention of postoperative infections in ophthalmic surgery. Ciprofloxacin and vancomycin-conjugated hyaluronic acid (HA) particles were prepared as drug carriers for sustained release of antibiotics. The antimicrobial effects of the released drugs were determined by disc-diffusion and macro-dilution tests at different times up to 2 weeks. Slow degradable HA particles were obtained with 35.2 wt% degradation within 21 days. The drug loading amount was increased by employing two sequential chemical linking (conjugation, 2C) and one physical absorption loading (A) procedures (2C + A processes) from 148 ± 8 to 355 ± 11 mg/g HA particles for vancomycin. The amounts of vancomycin and ciprofloxacin that were released linearly was estimated as 64.35 ± 7.35 and 25.00 ± 0.68 mg/g, respectively, from drug-conjugated HA particles in 100 h. Antimicrobial studies revealed that antibiotic-conjugated HA particles could inhibit the growth of microorganisms from 1 h to 1 week. The MBC values were measured as 0.25, 4.0, and 0.25 mg/mL against Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis, respectively, after 72 h incubation time. Cytotoxicity studies showed no difference between fibroblast growth or corneal thickness after 5 days with or without HA-antibiotic particles. The drug release studies and antimicrobial activity of antibiotic-loaded HA particles with time against various bacteria further revealed that HA particles are very effective in preventing bacterial infections. Likewise, cytotoxicity studies suggest that these particles pose no toxicity to eukaryotic cells, including corneal endothelium.

Titanium coating with mussel inspired polymer and bio-orthogonal chemistry enhances antimicrobial activity against Staphylococcus aureus.

Implant-associated infections present severe and difficult-to-treat complications after surgery, related to implant biofilm colonization. Systemic administration of antibiotics cannot reach sufficient concentrations at the infected site and may be toxic. Here we describe how mussel-inspired dendritic material coated on a titanium surface can locally activate a prodrug of daptomycin (pro-dapto) to treat methicillin-resistant Staphylococcus aureus. The mechanism of the prodrug activation is based on bio-orthogonal click chemistry between a tetrazine (Tz) and trans-cyclooctene (TCO). The former is attached to the dendritic polymer, while the later converts daptomycin into a prodrug. Characterization of the material's properties revealed that it is hydrophobic, non-toxic, and stable for a prolonged period of time. We envision that the titanium coated dendritic material will be able to improve the treatment of implant-associated infections by concentrating systemically administered antibiotic prodrugs, thus converting them into active localized medicines.

Localized mandibular infection affects remote in vivo bioreactor bone generation.

Mandibular reconstruction requires functional and aesthetic repair and is further complicated by contamination from oral and skin flora. Antibiotic-releasing porous space maintainers have been developed for the local release of vancomycin and to promote soft tissue attachment. In this study, mandibular defects in six sheep were inoculated with 106 colony forming units of Staphylococcus aureus; three sheep were implanted with unloaded porous space maintainers and three sheep were implanted with vancomycin-loaded space maintainers within the defect site. During the same surgery, 3D-printed in vivo bioreactors containing autograft or xenograft were implanted adjacent to rib periosteum. After 9 weeks, animals were euthanized, and tissues were analyzed. Antibiotic-loaded space maintainers were able to prevent dehiscence of soft tissue overlying the space maintainer, reduce local inflammatory cells, eliminate the persistence of pathogens, and prevent the increase in mandibular size compared to unloaded space maintainers in this sheep model. Animals with an untreated mandibular infection formed bony tissues with greater density and maturity within the distal bioreactors. Additionally, tissues grown in autograft-filled bioreactors had higher compressive moduli and higher maximum screw pull-out forces than xenograft-filled bioreactors. In summary, we demonstrated that antibiotic-releasing space maintainers are an innovative approach to preserve a robust soft tissue pocket while clearing infection, and that local infections can increase local and remote bone growth.

A dual PMMA/calcium sulfate carrier of vancomycin is more effective than PMMA-vancomycin at inhibiting Staphylococcus aureus growth in vitro.

Both antibiotic-impregnated poly(methyl acrylate, methyl methacrylate) (PMMA) and antibiotic-impregnated calcium sulfate have been successfully used as local antibiotic delivery vehicles for the management of chronic osteomyelitis. Here, we examined the antibiotic elution characteristics and antibacterial properties of a composite drug delivery system consisting of PMMA/calcium sulfate carrying vancomycin (dual carrier-v) against Staphylococcus aureus, with PMMA loaded with vancomycin (PMMA-v) as a control. Vancomycin gradually degraded from dual carrier-v and PMMA-v up to about 8 and 6 weeks, respectively. At different elution time points, the inhibition zones of the dual carrier-v were larger than the inhibition zones of the PMMA-v (P < 0.05). The colony inhibition rate of the dual carrier-v was 95.57%, whereas it was 77.87% for PMMA-v. Scanning electron microscopy was used to demonstrate biofilm formation on the surface of plates treated with vancomycin-unloaded PMMA, whereas there was no biofilm formation on the surface of plates treated with dual carrier-v or PMMA-v. The dual carrier-v was more effective at antibacterial adhesion at each time point after immersion in simulated body fluid as compared with PMMA-v (P < 0.05). In conclusion, our results suggest that the dual carrier-v can release higher concentrations of antibiotics and inhibit bacteria growth more effectively in vitro as compared with PMMA-v. The dual carrier-v thus may have potential as an alternative strategy for osteomyelitis management.

Reduced Graphene-Oxide-Embedded Polymeric Nanofiber Mats: An "On-Demand" Photothermally Triggered Antibiotic Release Platform.

The steady increase of antimicrobial resistance of different pathogens requires the development of alternative treatment strategies next to the oral delivery of antibiotics. A photothermally activated platform based on reduced graphene oxide (rGO)-embedded polymeric nanofiber mats for on-demand release of antibiotics upon irradiation in the near-infrared is fabricated. Cross-linked hydrophilic nanofibers, obtained by electrospinning a mixture of poly(acrylic acid) (PAA) and rGO, show excellent stability in aqueous media. Importantly, these PAA@ rGO nanofiber mats exhibit controlled photothermal heating upon irradiation at 980 nm. Nanofiber mats are efficiently loaded with antibiotics through simple immersion into corresponding antibiotics solutions. Whereas passive diffusion based release at room temperature is extremely low, photothermal activation results in increased release within few minutes, with release rates tunable through power density of the applied irradiation. The large difference over passive and active release, as well as the controlled turn-on of release allow regulation of the dosage of the antibiotics, as evidenced by the inhibition of planktonic bacteria growth. Treatment of superficial skin infections with the antibiotic-loaded nanofiber mats shows efficient wound healing of the infected site. Facile fabrication and implementation of these photothermally active nanofiber mats makes this novel platform adaptable for on-demand delivery of various therapeutic agents.