Sustained Release Of Antibiotics Research Articles

Release Kinetics of Doxycycline Encapsulated in Polylactoglycolide Scaffolds Using Supercritical Carbon Dioxide

Supercritical fluid encapsulation of doxycycline into aliphatic polyesters was used to fabricate bioresorbable antibacterial polylactoglycolide scaffolds. The distributions of doxycycline concentration on the surface and in the bulk of polymer structures were analyzed using high (≈1 μm) spatial resolution Raman spectroscopy. The release kinetics of doxycycline from these scaffolds into saline solution was studied. It is shown that, with the exception of the first 3 h, when about 15% of its total amount goes into the solution, the release of doxycycline occurs almost linearly. During the first day, the total yield of the antibiotic was about 22%. In 15 days (maximum observation time), the total amount of doxycycline released from polylactoglycolide scaffolds was about 70%. Thus, bioresorbable polymer scaffolds fabricated with supercritical carbon dioxide can be used for local sustained release of antibiotics, as well as for biologically active scaffolds for tissue engineering.

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 2weeks. Slow degradable HA particles were obtained with 35.2wt% degradation within 21days. 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±11mg/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±0.68mg/g, respectively, from drug-conjugated HA particles in 100h. Antimicrobial studies revealed that antibiotic-conjugated HA particles could inhibit the growth of microorganisms from 1h to 1week. The MBC values were measured as 0.25, 4.0, and 0.25mg/mL against Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis, respectively, after 72h incubation time. Cytotoxicity studies showed no difference between fibroblast growth or corneal thickness after 5days 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.

Recombinant Spider Silk-Silica Hybrid Scaffolds with Drug-Releasing Properties for Tissue Engineering Applications.

Fabricating biomaterials with antimicrobial activity to prevent the growth of detrimental microorganisms is of great scientific and practical interest. Here, composite materials comprising recombinant spider silk proteins and mesoporous silica nanoparticles (MSN) loaded with selected antibiotics and antimycotics are fabricated into films and hydrogels. The derived composite materials exhibit excellent antimicrobial properties with sustained release of antibiotics over the course of 15 days. Furthermore, antibiotics/antimycotics inclusion does not impair the cytocompatibility of the composite materials, all of which promote fibroblast cell adhesion and proliferation. Finally, processing of spider silk-MSN composite hydrogels using 3D printing is shown to enable the fabrication of patient-specific antimicrobial implants to prevent infection in the near future.

Sustaining Antibiotic Release from a Poly(methyl methacrylate) Bone-Spacer

One of the challenges in using a bone-spacer to cure infection is the fabrication of a material that can continuously release required antibiotics at effective concentrations for at least 4–6 weeks. Poly(methyl methacrylate) (PMMA) impregnated with antibiotics is one of the popularly used bone-spacer materials. Currently, improved sustained release of hydrophobic and hydrophilic antibiotics is needed for this material. Here, hydrophilic vancomycin (VAN) was encapsulated into calcium citrate (CC) particles and natural rice granules, and hydrophobic erythromycin (ERY) was encapsulated into ethyl cellulose and poly(lactic-co-glycolic acid) particles. The four antibiotic-loaded particles were each incorporated into the PMMA cement. The two unencapsulated drugs and all four drug-loaded particles distributed well in the obtained composites. PMMA composited with VAN-loaded CC showed prolonged VAN release at an effective concentration for more than 40 days, but the composite possessed lesser compressive strength than the PMMA with no drug. PMMA composited with unencapsulated ERY showed a better sustainment of drug release than those composited with encapsulated ERY. VAN elution from the VAN–CC–PMMA did not significantly affect the compressive strength of the material, whereas ERY elution from the ERY–PMMA composite significantly decreased the material’s mechanical strength.

In Situ Gelling Hydrogel with Anti-Bacterial Activity and Bone Healing Property for Treatment of Osteomyelitis.

Despite the development of progressive surgical techniques and antibiotics, osteomyelitis is a big challenge for orthopedic surgeons. The main aim of this study is to fabricate an in situ gelling hydrogel that permits sustained release of antibiotic (for control of infection) and growth factor (for induction of new bone formation) for effective treatment of osteomyelitis. An in situ gelling alginate (ALG)/hyaluronic acid (HA) hydrogel containing vancomycin (antibiotic) and bone morphogenetic protein-2 (BMP-2; growth factor) was prepared by simple mixing of ALG/HA/Na2HPO4 solution and CaSO4/vancomycin/BMP-2 solution. The release behaviors of vancomycin and BMP-2, anti-bacterial effect (in vitro); and therapeutic efficiency for osteomyelitis and bone regeneration (in vivo, osteomyelitis rat model) of the vancomycin and BMP-2-incorporated ALG/HA hydrogel were investigated. The gelation time of the ALG/HA hydrogel was controlled into approximately 4min, which is sufficient time for handling and injection into osteomyelitis lesion. Both vancomycin and BMP-2 were continuously released from the hydrogel for 6weeks. From the in vitro studies, the ALG/HA hydrogel showed an effective anti-bacterial activity without significant cytotoxicity for 6weeks. From an in vivo animal study using Sprague-Dawley rats with osteomyelitis in femur as a model animal, it was demonstrated that the ALG/HA hydrogel was effective for suppressing bacteria (Staphylococcus aureus) proliferation at the osteomyelitis lesion and enhancing bone regeneration without additional bone grafts. From the results, we suggest that the in situ gelling ALG/HA hydrogel containing vancomycin and BMP-2 can be a feasible therapeutic tool to treat osteomyelitis.

The Effect of Halloysite Addition on the Material Properties of Chitosan-Halloysite Hydrogel Composites.

Chitosan-based hydrogels are being widely used in biomedical applications due to their eco-friendly, biodegradable, and biocompatible properties, and their ability to mimic the extracellular matrix of many tissues. However, the application of chitosan hydrogels has been limited due to their inherent mechanical weakness. Halloysite nanotubes (HNTs) are naturally occurring aluminosilicate clay minerals and are widely used as a bulk filler to improve the performance characteristics of many polymeric materials. HNTs have also been shown to be a viable nanocontainer able to provide the sustained release of antibiotics, chemicals, and growth factors. This study’s objective was to develop a stable drug delivery chitosan/HNT nanocomposite hydrogel that is biocompatible, biodegradable, and provides sustained drug release. In this study, chitosan/HNTs hydrogels containing undoped or gentamicin-doped HNTs were combined in different wt./wt. ratios and cross-linked with tripolyphosphate. The effects of chitosan and HNTs concentration and combination ratios on the hydrogel surface morphology, degradability, and mechanical properties, as well as its drug release capability, were analyzed. The results clearly showed that the addition of HNTs improved chitosan mechanical properties, but only within a narrow range. The nanocomposite hydrogels provided a sustained pattern of drug release and inhibited bacterial growth, and the live/dead assay showed excellent cytocompatibility.

Electrospinning of silica nanoparticles-entrapped nanofibers for sustained gentamicin release

Sustained antibiotic release is important to prevent the infections after surgical treatments such as guided tissue regeneration (GTR). Electrospinning provides a simple way to fabricate nanofibers for drug delivery. In this study, a simple method to achieve sustained antibiotic release by introducing mesoporous silica nanoparticles (MSNs)with electrospinning is developed. The nanoparticles entrapped nanofibers (MSNs-PCL) were successfully fabricated, and a sustained release of gentamicin was demonstrated. The gentamicin loaded MSNs-PCL showed strong antimicrobial effects against E. coli, indicated the sustained release behavior and the retained bioactivity. The MSNs-PCL synthesized by electrospinning method shows great potential for biomedical applications such as fabricating GTR membranes.

Chitosan sponges as a sustained release carrier system for the prophylaxis of orthopedic implant-associated infections

The present investigation aims to study the chitosan sponge as a carrier matrix for the sustained antibiotic release system for the prophylaxis of orthopedic implant-associated infections (OIAIs). We have prepared sponges of three broad-spectrum antibiotics, namely vancomycin, ciprofloxacin and cefuroxime possessing different physicochemical properties. The blank, vancomycin, ciprofloxacin and cefuroxime loaded chitosan sponges were denoted as Blank-CH, CH-VAN, CH-CIP, and CH-CEF sponges. Chitosan sponges were assessed for morphology, drug-release, antibacterial potential, and preclinical evaluation using a rat subcutaneous implantation model. The results revealed that the physicochemical properties of the drug incorporated into the chitosan matrix play an important role in the morphology, degradation and drug release profile. Due to the highly hydrophilic properties of vancomycin, the CH-VAN sponge showed the highest swelling and fastest degradation profile. The CH-VAN sponge demonstrated the short-term release in contrast with the CH-CEF and CH-CIP sponges, which showed sustained release along with sustainable antibacterial activity. The preclinical evaluation proved that the CH-CIP and CH-CEF sponges were biodegradable, non-toxic and biocompatible. Further, the CH-CIP and CH-CEF sponges were able to maintain minimum plasma concentration with higher local tissue antibiotic concentration. Therefore, the CH-CIP and CH-CEF sponges could be promising candidates for the long-term prophylaxis of OIAIs.

Matryoshka-type gastro-resistant microparticles for the oral treatment of Mycobacterium tuberculosis.

Production of Matryoshka-type gastroresistant microparticles containing antibiotic-loaded poly lactic-co-glycolic acid (PLGA) nanoparticles (NP) against Mycobacterium tuberculosis. The emulsification and evaporation methods were followed for the synthesis of PLGA-NPs and methacrylic acid-ethyl acrylate-based coatings to protect rifampicin from degradation under simulated gastric conditions. The inner antibiotic-loaded NPs here reported can be released under simulated intestinal conditions whereas their coating protects them from degradation under simulated gastric conditions. The encapsulation does not hinder the antituberculosis action of the encapsulated antibiotic rifampicin. A sustained antibiotic release could be obtained when using the drug-loaded encapsulated NPs. Compared with the administration of the free drug, a more effective elimination of M. tuberculosis was observed when applying the NPs against infected macrophages. The antibiotic-loaded PLGA-NPs were also able to cross an in vitro model of intestinal barrier.

Low-intensity pulsed ultrasound enhances antibiotic release of gentamicin-loaded, self-setting calcium phosphate cement.

ObjectiveThis study aimed to investigate the effect of low-intensity pulsed ultrasound on antibiotic release from gentamicin-loaded, self-setting calcium phosphate cement.MethodsA gentamicin-loaded calcium phosphate cement cylinder was eluted in stimulated body fluid. Low-intensity pulsed ultrasound (46.5 kHz, 200 mW/cm2) was used to produce a sinusoidal wave in the experimental group. Non-gentamicin calcium phosphate cement was used in the control group.ResultsThe transient concentration and cumulatively released percentage of gentamicin in the ultrasound group were higher than those in control group at every time point. The duration of gentamicin concentrations over the level of the minimum inhibitory concentration was significantly prolonged in the ultrasound group compared with the control group. Antibacterial efficacy of gentamicin in the ultrasound group was significantly better than that in the control group with the same concentration of gentamicin.ConclusionLow-intensity pulsed ultrasound enhances antibiotic release, providing sustained antibiotic release at high concentrations. This increases the antibacterial effect of gentamicin.

Influence of chemical and physical conditions in selection of Gluconacetobacter hansenii ATCC 23769 strains with high capacity to produce bacterial cellulose for application as sustained antimicrobial drug-release supports.

Obtain varieties of Gluconacetobacter hansenii from original strain ATCC 23729 with greater efficiency to produce bacterial cellulose (BC) membrane with better dry mass yield for application as support of sustained antimicrobials' drug release. Application of different chemical and physical conditions (pH, temperature and UV light exposure) to obtain different G. hansenii varieties with high capacity to produce BC membranes. Characterization of the G. hansenii variants was performed by scanning electron microscopy (SEM) and optical microscopy of the colony-forming units. BC membrane produced was characterized by SEM, infrared spectroscopy and X-ray diffraction. The BC produced by variants isolated after incubation at 35°C showed elevated dry mass yield and high capacity of retention and sustained release of ceftriaxone antibiotic with the produced BC by original G. hansenii ATCC 23769 strain subjected to incubation at 28°C and with commercial BC. The application of different chemical and physical conditions constitutes an important method to obtain varieties of micro-organisms with dissimilar metabolism advantageous in relation to the original strain in the BC production. These results demonstrate the importance of invivo studies for the application, in medicine, of BC membranes as support for antimicrobial-sustained release for the skin wound treatment.

Hydroxyapatite Functionalized with 1,2-Hydroxypropyl-β-Cyclodextrin as Scaffolds for Antibiotic Release in Bone Tissue

Background: The difficulty of eliminating bacteria infecting bone tissue during bone healing treatments or surgery makes it desirably to develop solid scaffolds capable of sustained release of antibiotics to achieve the regeneration of the damaged tissue. Methods: With this function in view, in this work we prepared HA scaffolds functionalized with1,2- Hydroxypropyl-β-Cyclodextrin to increase the loading and sustained release for ciprofloxacin. Results: The lowest amount of CD was sufficient to fabricate HA functionalized microparticles and allowing for the CPX loading to be increased more than 40 times with respect to the non-functionalized HA particles. Spray-drying process rendered spherical particles with irregular surface that improved the release and the solubility of low soluble CPX in pH 7.4 medium in form of free drug and cyclodextrin complexes although free cyclodextrins were also released to the medium. Conclusion: It is concluded that the synthesized microparticles based on HA functionalized with Hydroxypropyl -β-Cyclodextrin merit further investigation to be used as platform for delivering antibiotics in bone regeneration.

Stimulus-responsive zinc oxide-functionalized macromolecular humic acid nanocarrier for enhancement of antibacterial activity of ciprofloxacin hydrochloride

Macromolecular of naturally occurring humic acid (HA) have garnered interest in the chemical, biological and medicine industry owing to their unique behavior, i.e., strong adsorptive and non-toxic nature. Here, we investigated the functionalization of organic (HA) with inorganic (ZnO) hybrid nanoparticles for topical and site-targeted delivery of ciprofloxacin by simple emulsification techniques. Ciprofloxacin (CIPRO)-encapsulated hybrid nanocarrier constitute an attractive novel drug delivery vehicle for sustained release of antibiotics to bacterial infection sites in an extended and controlled manner. The analytical characteristics of the designed system were thoroughly investigated by FTIR, XRD, SEM/EDAX, and TEM. The drug release of ciprofloxacin over 24h was 87.5%, 98.03%, 97.44%, and 97.24% for pH2.5, 5.5, 6.8, and 8.0, respectively. The antibacterial activities results confirmed that the CIPRO-encapsulated hybrid nanocarrier showed excellent growth inhibition against microorganisms. This hybrid nanocarrier loaded with antibiotics represents a promising approach for targeted and controlled drug delivery to infected sites.

Embedding of Ag by Porous Substitute on Glazed Ceramics for Sustained Antibiotic Release

ABSTRACTSustained antibiotic release of Ag ions on glazed ceramics has been addressed by MCM-41. For this purpose, the feasibility of sol-gel method and hydrothermal method for Ag-MCM-41 preparation has been discussed. The characterizations of the materials were done by scanning electron microscopy, energy dispersive spectroscopy, nitrogen adsorption-desorption isotherms and X-ray photoelectron spectroscopy. Results indicated that Ag element (AgO, Ag2O, Ag2O3 and metallic Ag) was loaded on the surface of S-Ag-MCM-41 (sol-gel method), but in the pores of H-Ag-MCM-41 (hydrothermal method). The inside loading of Ag in H-Ag-MCM-41 shows more positive effect for stable antibacterial property against E.coli as well as Ag release of glazed ceramics, rather than S-Ag-MCM-41. The Ag release of S-Ag-MCM-41 decreased from 0.063-0.072 to 0.028-0.038 mg.L–1 after one cycle, much larger as compared to H-Ag-MCM-41 (from 0.032-0.063 to 0.031-0.033).

Mesoporous silica nanoparticles/gelatin porous composite scaffolds with localized and sustained release of vancomycin for treatment of infected bone defects.

Treatment of infected bone defects still remains a formidable clinical challenge, the design of bone implants with the controlled release of antibiotics is now regarded as a powerful strategy for infection control and bone healing. In this study, we fabricated a composite scaffold based on vancomycin (Van) loaded mesoporous silica nanoparticles (Van@MSNs) and a gelatin matrix. The microscopic structure of the gelatin-based composite scaffolds was characterized as highly porous. By the addition of MSNs, an enhancement in the compression property of MSNs-incorporated composite scaffolds was observed. The Van could release from the Van@MSNs incorporated composite scaffold in a sustained-release manner with a minimal burst, and thus effectively inhibit the growth of Staphylococcus aureus in a subsequent in vitro antibacterial study. In addition, the drug-loaded composite scaffold showed no unfavorable effects on the proliferation and differentiation of bone mesenchymal stem cells (BMSCs), confirming good biocompatibility. Moreover, in vivo results demonstrated that the antibiotic-loaded composite scaffold could significantly reduce bacterial contamination while promoting bone healing. Thus, our results suggest that the fabricated Van@MSNs/Gelatin composite scaffold with a localized and sustained release of antibiotics is a promising biomaterial for treating infected bone defects.

An Advanced Multifunctional Hydrogel‐Based Dressing for Wound Monitoring and Drug Delivery

Wound management is a major global challenge and poses a significant financial burden to the healthcare system due to the rapid growth of chronic diseases such as diabetes, obesity, and aging population. The ability to detect pathogenic infections and release drug at the wound site is of the utmost importance to expedient patient care. Herein, this study presents an advanced multifunctional dressing (GelDerm) capable of colorimetric measurement of pH, an indicator of bacterial infection, and release of antibiotic agents at the wound site. This study demonstrates the ability of GelDerm to detect bacterial infections using in vitro and ex vivo tests with accuracies comparable to the commercially available systems. Wireless interfaces to digital image capture hardware such as smartphones serve as a means for quantitation and enable the patient to record the wound condition at home and relay the information to the healthcare personnel for following treatment strategies. Additionally, the dressing is integrated within commercially available patches and can be placed on the wound without chemical or physical irritation. This study demonstrates the ability of GelDerm to eradicate bacteria by the sustained release of antibiotics. The proposed technology holds great promise in managing chronic and acute injuries caused by trauma, surgery, or diabetes.

Infection prevention using affinity polymer-coated, synthetic meshes in a pig hernia model

BackgroundGiven concern for hernia mesh infection, surgeons often use biologic mesh which may provide reduced risk of infection but at the cost of decreased repair durability. We evaluated mesh coating to provide sustained release of antibiotics to prevent prosthetic mesh infection and also allow a durable repair. Materials and methodsCyclodextrin-based polymer was crosslinked onto multifilament polyester mesh and loaded with vancomycin (1.75 mg/cm2). Pigs received modified meshes (n = 6) or normal, untreated meshes (n = 4), which were implanted into acute 10 × 5 cm ventral hernia, then directly inoculated with 106 colony-forming unit (CFU) of methicillin-resistant Staphylococcus aureus (MRSA). These were compared to animals receiving normal, uninfected mesh. All mesh was secured in an underlay bridge manner, and after 30 d, the abdominal wall was removed for quantitative bacterial culture and biomechanical analysis. ResultsAll animals survived 30 d. All six animals with coated mesh cleared MRSA infection. The four control animals did not clear MRSA (P = 0.005). Quantitative bacterial load was higher in standard mesh versus drug-delivery mesh group (2.34 × 104versus 80.9 CFU/gm). These data were log10-transformed and analyzed by Welch's t-test (P = 0.001). Minimum number of CFUs detectable by assay (300) was used instead of zero. Biomechanical analysis of controls (1.82 N/mm infected; 1.71 N/mm uninfected) showed no difference to the modified meshes (1.31 N/mm) in tissue integration (P = 0.15). ConclusionsWe successfully prevented synthetic mesh infection in a pig model using a cyclodextrin-based polymer to locally deliver vancomycin to the hernia repair site and clearing antibiotic-resistant bacteria. Polymer coating did not impact the strength of the hernia repair.

Thermosensitive hydrogel as an in situ gelling antimicrobial ocular dressing

Microbial keratitis is a severe ocular condition and one of the most prevalent causes of corneal scarring and associated blindness worldwide. Risk factors include contact lens use, ocular trauma, ocular surface disease and immunosuppression. Initial clinical management mandates intensive (hourly or more frequent) topical administration of broad spectrum antimicrobial therapy for at least 48h, which may require hospital admission, followed by tailored therapy based on microbiological investigation and the institution of strategies to reduce inflammation and promote healing. In this work we report an ocular wound dressing which can encapsulate and give sustained release of different antibiotics. The use of this dressing would allow patients to have eye drops on a 4 hourly basis, thereby facilitating treatment compliance and reducing hospital admissions.

Development of Absorbable, Antibiotic-Eluting Sutures for Ophthalmic Surgery.

PurposeTo develop and evaluate an antibiotic-eluting suture for ophthalmic surgery.MethodsWet electrospinning was used to manufacture sutures composed of poly(L-lactide), polyethylene glycol (PEG), and levofloxacin. Size, morphology, and mechanical strength were evaluated via scanning electron microscopy and tensile strength, respectively. In vitro drug release was quantified using high performance liquid chromatography. In vitro suture activity against Staphylococcus epidermidis was investigated through bacterial inhibition studies. Biocompatibility was determined via histological analysis of tissue sections surrounding sutures implanted into Sprague-Dawley rat corneas.ResultsSutures manufactured via wet electrospinning were 45.1 ± 7.7 μm in diameter and 0.099 ± 0.007 newtons (N) in breaking strength. The antibiotic release profile demonstrated a burst followed by sustained release for greater than 60 days. Increasing PEG in the polymer formulation, from 1% to 4% by weight, improved drug release without negatively affecting tensile strength. Sutures maintained a bacterial zone of inhibition for at least 1 week in vitro and elicited an in vivo tissue reaction comparable to a nylon suture.ConclusionsThere is a need for local, postoperative delivery of antibiotics following ophthalmic procedures. Wet electrospinning provides a suitable platform for the development of sutures that meet size requirements for ophthalmic surgery and are capable of sustained drug release; however, tensile strength must be improved prior to clinical use.Translational RelevanceNo antibiotic-eluting suture exists for ophthalmic surgery. A biocompatible, high strength suture capable of sustained antibiotic release could prevent ocular infection and preclude compliance issues with topical eye drops.

Fabrication of egg shell-like nanovesicles from a thiocoumarin-based ε-amino ester: a potential carrier.

Nanoscale egg shell-like drug delivery systems from methyl 6-amino-2-oxo-2H-thiochromene-3-carboxylate, a thiocoumarin-based ε-amino ester, have been investigated as potential candidates for drug delivery vehicles. X-ray crystallography reveals that the ε-amino ester adopts a planar structure and self-associates to form a four-membered ring-like porous architecture through multiple N-HO and C-HS intermolecular hydrogen bonding interactions. At higher order packing, the ε-amino ester forms an anti parallel sheet-like structure by intermolecular hydrogen bonding as well as face-to-face π-π stacking interactions. Field emission scanning electron microscopy (FE-SEM) revealed that the ε-amino ester exhibits an egg shell-like porous nanovesicle morphology. These egg shell-like nanovesicles have been used as a potential carrier for the bacteriostatic antibiotic sulfamethoxazole. The spectroscopic studies as well as the growth inhibition of E. coli exhibit that the ε-amino ester-sulfamethoxazole formulation leads to pH responsive sustained release of the drug. This report highlights the utility of designer amino acid-drug supramolecular combinations.