Low-density polypropylene meshes coated with resorbable and biocompatible hydrophilic polymers as controlled release agents of antibiotics

Abstract

The application of bioactive meshes in abdominal surgery for the repair of hernias is an increasing clinical activity in a wide sector of the population. The main secondary effect is the appearance of infections from bacteria, specifically Staphylococcus aureus and S. epidermidis. This paper describes the development and application of low-density polypropylene meshes coated with a biocompatible and resorbable polymer as a controlled release system of the antibiotic vancomycin. The polymeric coating (a non-cross-linked copolymer of 2-hydroxyethyl methacrylate and 2-acrylamido-2-methylpropanesulfonic acid) has a thickness of 14–15 μm and contains 0.32 mg cm⁻² of the antibiotic vancomycin. The in vitro experiments demonstrate the excellent inhibitory character of the coated meshes loaded with the antibiotic, following the standard protocol of inhibition of halo in agar diffusion test. This inhibitory effect is maintained for a relatively long period (at least 14 days) with a low concentration of antibiotic. The acrylic polymer system regulates the release of the antibiotic with a rate of 24 μg h⁻¹, due to its slow dissolution in the medium. Experiments in vivo, based on the implantation of coated meshes, demonstrate that the system controls the infection in the animal (rabbits) for at least 30 days. The concentration of antibiotic in the blood stream of the rabbits was below the detection limit of the analytical technique (<1–2 μg ml⁻¹), which demonstrates that the antibiotic is released in the local area of the implant and remains concentrated at the implantation site, without diffusion to the blood stream. The systems can be applied to other medical devices and implants for the application of new-generation antibiotics in a controlled release and targeted applications.

Introduction

Hernia repair is one of the most frequently performed surgical procedures—midline laparotomy produces incisional hernias at a rate of 2–9% [1]; the placement of a synthetic mesh is the standard technique of reinforcement. The application of a polypropylene mesh by Uscher [2] was considered one of the greatest advances in this field. Surgical techniques have progressed, through the application of advanced designs and materials such as synthetic meshes [3]. The function of meshes is to provide mechanical closure to the defect and to induce strong scar tissue with good biocompatibility and low cell adhesion [4]. There is a variety of meshes made of synthetic resorbable materials, and non-resorbable or organic material derived from human or pig tissues. Meshes of polypropylene (PP) with controlled net size have been applied extensively because of polypropylene’s high biocompatibility, inert character, morphology and other properties [5]. Clinical complications as a result of the application of surgical meshes include inflammatory response, irregular or low formation of scar tissue and, most importantly, the appearance of infections; these have been estimated to occur in about 3–4% of inguinal hernias and 6–10% of incisional hernias [6]. This is relevant because of the considerable number of surgical procedures. In the USA alone, infection affects more than 30,000 patients a year with inguinal hernias and more than 3000 patients a year with incisional hernias. The more common microorganisms involved in these bacterial infections are Staphylococcus aureus (Sa) and S. epidermidis (Se), together with Gram-negative species including Escherichia coli and Pseudomonas aeruginosa [7].

The adhesion of bacteria to the surface of a biomaterial is a crucial step in the pathogenesis of infection. Some microorganisms are capable of forming a biofilm on the mesh that protects the immune system and the action of the antibiotics [8]. Once the mesh has been infected, no treatment is possible and it is necessary to remove the prosthesis. The administration of single-dose prophylactic systemic antibiotics is a standard procedure and has proven efficacy in surgery of implants, including orthopedic and breast prostheses [9]. In addition to the state of the patient, the infection is related to the design, structure, composition and morphology of the mesh [10], and is more frequent for microporous implants and multifilament meshes [11], [12].

The infection of biomaterials for hernia repair is an increasing clinical problem, because of the noticeable increase of the repair surgery of the abdominal wall. Primary and secondary hernias are very frequent, even after the application of minimal invasive techniques. The application of biomaterials is necessary to minimize the rate of relapse [7], [13].

The best way to treat the infection of an implant is to prevent the colonization of microorganisms in the early stages, avoiding the formation of biofilm [14] and the colonization of the biomaterial by pathogens [15]. An adequate method is the modification of the implant surface with a biocompatible and resorbable polymer coating for the controlled release of the antibiotic just in the site of action [16].

We consider that the application of coatings based on hydrophilic and biocompatible resorbable acrylic polymers could offer an excellent system for the control of infections on site. Our experience in the preparation of slow resorbable hydrosoluble systems based on non-cross-linked 2-hydroxyethyl methacrylate–2-acrylamido-2-methylpropanesulfonic acid (HEMA–AMPS) copolymers indicates that this system offers a good alternative for the preparation of bioactive coated meshes.