Meital Zilberman

Antibiotic-eluting medical devices for various applications

Infection is defined as a homeostatic imbalance between the host tissue and the presence of microorganisms. It is associated with a large variety of wound occurrences ranging from traumatic skin tears and burns to chronic ulcers and complications following surgery and device implantations. If the wound setting manages to overcome the microorganism invasion by a sufficient immune response then the wound should heal. If not, the formation of an infection can seriously limit the wound healing process. Evidence of increasing bacterial resistance is on the rise, and complications associated with infections are therefore expected to increase. The main goal in treating various types of wound infections is to decrease the bacterial load in the wound to a level that enables wound healing processes to take place. Conventional systemic delivery of antibiotics entails poor penetration into ischemic and necrotic tissue and can cause systemic toxicity with associated renal and liver complications, which result in a need for hospitalization for monitoring. Alternative local delivery of antibiotics by either topical administration or by a delivery device may enable the maintenance of a high local antibiotic concentration for an extended duration of release without exceeding systemic toxicity. The present review describes approaches for local prevention of bacterial infections based on antibiotic-eluting medical devices. These devices include bone cements, fillers and coatings for orthopedic applications, wound dressings based on synthetic and natural polymers, intravascular devices, vascular grafts and periodontal devices. Part of the review is dedicated to our novel composite drug-eluting fibers and structured drug-eluting films, which are designed to be used as basic elements of various devices. In this review emphasis is placed on processing techniques, microstructure, drug release profiles, biocompatibility and other relevant aspects necessary for advancing the therapeutic field of antibiotic-eluting devices.

In vitro microbial inhibition and cellular response to novel biodegradable composite wound dressings with controlled release of antibiotics

About 70% of all people with severe burns die from related infections, despite advances in treatment regimens and the best efforts of nurses and doctors. Although silver-eluting wound dressings are available for addressing this problem, there is growing evidence of the deleterious effects of such dressings in delaying the healing process owing to cellular toxicity. A new concept of antibiotic-eluting composite wound dressings is described here. These dressings are based on a polyglyconate mesh coated with a porous poly-(dl-lactic-co-glycolic acid) matrix loaded with antibiotic drugs. The effect of antibiotic release on bacterial inhibition was studied, and cell cytotoxicity was examined. The dressings resulted in a 99.99% decrease in the viable counts of Pseudomonas aeruginosa and Staphylococcus albus at very high initial inoculations of 10⁷-10⁸ CFU ml⁻¹ after only 1 day, while such a decrease in Staphylococcus aureus was obtained within 3 days. Bacterial inhibition zones around the dressing material were found to persist for 2 weeks, indicating a long-lasting antimicrobial effect. Despite severe toxicity to bacteria, the dressing material was found to have no toxic effect on cultured fibroblasts, indicating that the new antibiotic-eluting wound dressings represent an effective option for selective treatment of bacterial infections.

Antibiotic-eluting bioresorbable composite fibers for wound healing applications: Microstructure, drug delivery and mechanical properties

Novel antibiotic-eluting composite fibers designed for use as basic wound dressing elements were developed and studied. These structures were composed of a polyglyconate core and a porous poly(dl-lactic-co-glycolic acid) shell loaded with one of three antibiotic drugs: mafenide acetate, gentamicin sulphate and ceftazidime pentahydrate. The shell was prepared by the freeze-drying of inverted emulsions. The fiber investigation focused on the effects of the emulsions formulation on the shell microstructure and on the resulting profile of drug release from the fibers. Albumin was found to be the most effective surfactant for stabilizing the inverted emulsions and also to have a beneficial holdup effect on the release kinetics of the hydrophilic antibiotic drugs, especially mafenide acetate, probably through a specific interaction. An increase in the organic:aqueous phase ratio, polymer content or molecular weight of the host polymer resulted in a decrease in the burst release and a more moderate release profile due to changes in shell microstructure. The first two parameters were found to be more effective than the third. The diverse release profiles obtained in the current study and the good mechanical properties indicate that our new composite fibers have good potential for use in wound healing applications.

Novel soy protein wound dressings with controlled antibiotic release: mechanical and physical properties.

Naturally derived materials are becoming widely used in the biomedical field. Soy protein has advantages over various types of natural proteins employed for biomedical applications due to its low price, non-animal origin and relatively long storage time and stability. In the current study soy protein isolate (SPI) was investigated as a matrix for wound dressing applications. The antibiotic drug gentamicin was incorporated into the matrix for local controlled release and, thus, protection against bacterial infection. Homogeneous yellowish films were cast from aqueous solutions. After cross-linking they combined high tensile strength and Youngs modulus with the desired ductility. The plasticizer type, cross-linking agent and method of cross-linking were found to strongly affect the tensile properties of the SPI films. Selected SPI films were tested for relevant physical properties and the gentamicin release profile. The cross-linking method affected the degree of water uptake and the weight loss profile. The water vapor transmission rate of the films was in the desired range for wound dressings (∼2300 g m(-2) day(-1)) and was not affected by the cross-linking method. The gentamicin release profile exhibited a moderate burst effect followed by a decreasing release rate which was maintained for at least 4 weeks. Diffusion was the dominant release mechanism of gentamicin from cross-linked SPI films. Appropriate selection of the process parameters yielded SPI wound dressings with the desired mechanical and physical properties and drug release behavior to protect against bacterial infection. These unique structures are thus potentially useful as burn and ulcer dressings.

Composite alginate hydrogels: An innovative approach for the controlled release of hydrophobic drugs.

We present an innovative methodology for the sustained delivery of hydrophobic drugs using composite hydrogels, prepared by embedding oil-in-water microemulsions in hydrophilic hydrogels. The hydrophobic nature of the microemulsion core enhances the solubilization of hydrophobic drugs, while the crosslinked matrix could be readily used as a solid controlled delivery vehicle. A microemulsion was formulated from pharmaceutical accepted components; the droplets diameter was shown to be about 10nm by dynamic light scattering, cryo-transmission electron microscopy and small-angle X-ray scattering (SAXS). Combining the microemulsion with alginate solution and crosslinking with calcium ions resulted in a clear hydrogel. A model hydrophobic drug, Ketoprofen, precipitated from the alginate hydrogel, but the drug-containing composite hydrogel was clear and macroscopically homogeneous. The nanostructure was investigated by SAXS; scattering plots indicate that oil droplets exist in the composite hydrogel. Release profiles of the drug from the composite hydrogel with various concentrations of polymer and crosslinker demonstrate the applicability of this system as a controlled delivery vehicle, and suggest that the release rate is governed not by the microemulsion structure but, rather, by the network properties. Furthermore, it was demonstrated that the release rate could be tailored for a specific application utilizing different alginate and calcium concentrations. The generalization of the methodology of including hydrophobic drugs in composite gels is discussed.

Novel biodegradable composite wound dressings with controlled release of antibiotics: Microstructure, mechanical and physical properties

Wound dressings aim to restore the milieu required for skin regeneration and protect the wound from environmental threats, including penetration of bacteria. The dressings should be easy to apply and remove and maintain a moist healing environment. In this study, novel biodegradable composite wound dressings based on a polyglyconate mesh and a porous PDLGA binding matrix were developed and studied. These novel dressings were prepared by dip-coating woven meshes in inverted emulsions, followed by freeze-drying. Their investigation focused on the microstructure, mechanical and physical properties, and the release profile of the antibiotic drug ceftazidime from the binding matrix. The mechanical properties of our wound-dressing structures were found to be superior, combining relatively high tensile strength and ductility, which changed only slightly during 3 weeks of incubation in an aqueous medium. The parameters of the inverted emulsion, the organic-aqueous phase ratio, and the type of surfactant used for stabilizing the emulsion were found to affect the microstructure of the binding matrix and the resulting properties, i.e., water absorbance, water vapor transmission rate, and drug-release profile from the binding matrix. Appropriate selection of these parameters can yield composite structures that have the desired physical properties and drug release behavior. Thus, these unique structures are potentially very useful as burn and ulcer dressings.

Novel antibiotic-eluting wound dressings: An in vitro study and engineering aspects in the dressing's design

Wound dressings aim to restore the milieu required for skin regeneration by protecting the wound from environmental threats, including penetration of bacteria, and by maintaining a moist healing environment. A wide variety of wound dressing products targeting various types of wounds and different aspects of the wound healing process are currently available on the market. Ideally, a dressing should be easy to apply and remove, and its design should meet both physical and mechanical requirements; namely water absorbance and transmission rate, handleability and strength. In this article, our novel biodegradable antibiotic-eluting wound dressings are described and the engineering aspects in the design are emphasized. These unique new wound dressings are based on a polyglyconate mesh, coated with a porous Poly(dl-lactic-co-glycolic acid) matrix. They demonstrated excellent mechanical and physical properties and desired release profiles of antibiotic drugs which enable bacterial inhibition. Hence, a new generation of wound dressings is now emerging with clear benefits. These include better protection against infection and reducing the need for frequent dressing changing.

Structured drug-loaded bioresorbable films for support structures

Bioresorbable films can serve simultaneously as anatomic support structures and as drug delivery platforms. In the present study, bioresorbable PLLA films containing dexamethasone were developed through solution processing. The effect of processing parameters on the film morphology and the resulting mechanical properties was studied. A model describing the structuring of these films is suggested. Generally, the solvent evaporation rate determines the kinetics of drug and polymer crystallization and thus, both the mode of drug dispersion in the polymer and the resulting mechanical properties. Two types of structured films were studied: (1) a polymer film with drug located on its surface, obtained due to drug skin formation accompanied by a later polymer core formation; and (2) a polymer film with small drug particles and crystals distributed within the bulk, obtained by parallel solidification of the two components. A prototypical application of these films is an expandable biodegradable support structure (stent), which we have developed. This stent demonstrated good initial mechanical properties. The film structure has only a minor effect on the stent radial compression strength, but more significantly affects the tensile mechanical properties.

Long-term in vitro study of paclitaxel-eluting bioresorbable core/shell fiber structures

Paclitaxel-eluting bioresorbable core/shell fiber structures for stent applications and local cancer treatment were developed and studied. These structures were composed of a polyglyconate core and a porous PDLGA shell loaded with the anti-proliferative agent paclitaxel, prepared using freeze drying of inverted emulsions. The investigation of these new composite fibers focused on the effects of the emulsions composition (formulation) and process kinetics on the long-term drug release from the fibers, in light of the shells morphology and degradation profile. Paclitaxel release from the porous shell was relatively slow due to its extremely hydrophobic nature. It exhibited three phases of release, which corresponded to the degradation profile of the host PDLGA. We found that the effect of the emulsion formulation on the release profile is more significant than the effect of the process kinetics. The copolymer composition had the most dominant effect on the drug release profile from the composite fibers. The polymer content also affected the release profile, whereas the drug content and the organic:aqueous phase ratio resulted in minor effects. Emulsions with a less hydrophobic nature are favorable for effective controlled release of the hydrophobic paclitaxel from the porous shell.

Drug delivery from gelatin-based systems

Introduction: Carriers for controlled drug release offer many advantages compared with conventional dosage forms. Gelatin has been investigated extensively as a drug delivery carrier, due to its properties and history of safe use in a wide range of medical applications. Areas covered: Gelatin was shown to be versatile due to its intrinsic features that enable the design of different carrier systems, such as microparticles and nanoparticles, fibers and even hydrogels. Gelatin microparticles can serve as vehicles for cell amplification and for delivery of large bioactive molecules, whereas gelatin nanoparticles are better suited for intravenous delivery or for drug delivery to the brain. Gelatin fibers contain a high surface area-to-volume ratio, whereas gelatin hydrogels can trap molecules between the polymer’s crosslink gaps, allowing these molecules to diffuse into the blood stream. Another interesting area is the combination of tissue bioadhesive-based gelatin with controlled drug release for pain management and wound healing. Expert opinion: The modification of gelatin and its combinations with other biomaterials have demonstrated the flexibility of these systems and can be employed for meeting the challenges of finding ideal carrier systems that enable specific, targeted and controlled release in response to demands in the body.