Emilio Bucio

Medical devices modified at the surface by γ-ray grafting for drug loading and delivery

Importance of the field: Medical devices with the capability of hosting drugs are being sought for prophylaxis and treatment of inflammatory response and microbial colonization and proliferation that are associated with their use. Areas covered in this review: This review analyzes the interest of γ-ray irradiation for providing medical devices with surfaces able to load drugs and to deliver them in a controlled way. The papers published in the last 20 years on the subject of γ-ray irradiation methods for surface functionalization of polymers and their application for developing medicated medical devices are discussed. What the reader will gain: The information reported may help to gain insight to the state-of-the-art of γ-ray irradiation approaches and their current advantages/limitations for tailoring the surface of medical devices to fit preventive and curative demands. Take home message: Grafting of polymer chains able to establish specific interactions with the drug, grafting of stimuli-responsive networks that regulate drug diffusion through the hydrogel-type surface as a function of the surrounding conditions, and grafting of cyclodextrins that control uptake and delivery through the affinity constant of inclusion complexes have been revealed as efficient approaches for endowing medical devices with the capability of also acting as drug delivery systems.

Polypropylene grafted with smart polymers (PNIPAAm/PAAc) for loading and controlled release of vancomycin

New smart surface-modified polypropylene (PP) was prepared for improving the loading and the sustained delivery of vancomycin and, thus, reducing the risk of biofilm formation when used as component of biomedical devices. Isothermal titration calorimetry (ITC) served for screening the most suitable monomers for grafting; the drug preferentially bonding to ionized acrylic acid (AAc). A net-PP-g-PNIPAAm-inter-net-PAAc was synthesized by first grafting and cross-linking of N-isopropylacrylamide onto PP films and then interpenetrating a second network by redox polymerization and cross-linking of AAc. PP-g-PAAc slabs were prepared by grafting AAc and, optionally, cross-linking. The amount and composition of grafted polymer (FTIR-ATR), morphology (SEM), temperature- and pH-responsiveness (swelling measurements), thermal behavior (DSC), friction coefficient (rheometry), drug loading and release rate, and effect against methicillin-resistant Staphylococcus aureus (MRSA) biofilms (modified robbins device) were evaluated. Grafting of AAc notably decreased the friction coefficient from 0.28+/-0.03 to 0.05+/-0.02 and enhanced the vancomycin loading (up to 2.5mg/cm(2)). Drug-loaded films showed a pH-dependent release rate, sustaining the release in pH 7.4 aqueous media at 37 degrees C for several hours. All drug-loaded films reduced biofilm formation by MRSA; the anti-biofilm effect being statistically significant (91.7% reduction, alpha<0.05) for PP-g-PAAc with the thinnest grafting layer.

Cyclodextrin-functionalized biomaterials loaded with miconazole prevent Candida albicans biofilm formation in vitro.

Polyethylene (PE) and polypropylene (PP) were functionalized at their surfaces with cyclodextrins (CDs) in order to prevent the adhesion and proliferation of Candida albicans on medical devices made from these polymers. The surface functionalization involved the grafting of glycidyl methacrylate (GMA) after oxidative gamma-ray pre-irradiation, followed by the attachment of beta-CD and HP-beta-CD to PE-g-GMA and PP-g-GMA surfaces. The yield of CD functionalization directly depended on the amount of GMA grafted. The presence of CDs on the surface of the polymers did not compromise their cell compatibility, but remarkably changed their protein adsorption profile. In contrast to unmodified PE and PP that adsorb significant amounts of fibrinogen ( approximately 0.047 mg cm(-2)) but not albumin, the CD-modified polyethers promoted the adsorption of albumin (between 0.015 and 0.155 mg cm(-2)) and reduced the adsorption of fibrinogen. Furthermore, functionalization with CDs provided PE and PP with the capability to incorporate the anti-fungal drug miconazole (up to 0.27 mg cm(-2)), leading to reduced biofilm formation by C. albicans in an in vitro biofilm model system. Overall, the results of the work indicate that the novel approach for functionalization of PE and PP is potentially useful to reduce the likelihood of foreign body-related infections.

Cyclodextrin-functionalized polyethylene and polypropylene as biocompatible materials for diclofenac delivery

Polyethylene (PE) and polypropylene (PP) were surface functionalized with beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) with the aim of providing PE and PP with the capability of behaving as drug delivery systems. Functionalization was carried out according to a two-step procedure: (i) glycidyl methacrylate (GMA) was grafted by means of gamma radiation and (ii) the epoxy groups of GMA reacted with the hydroxyl groups of CDs forming ether bonds. For a fix radiation dose and GMA concentration, grafting yield (ranging from 1 to 100 micromol GMA cm(-2)) depended on the time during which the preirradiated PE and PP films and slabs were immersed in the GMA solution. CD grafting (from 0.013 to 0.734 micromol cm(-2)) was confirmed by infrared analysis, DSC and the organic compound approach (using 3-methylbenzoic acid as a probe). Functionalization with CDs rendered as highly cytocompatible materials as the starting ones, did not cause relevant changes in the water contact angle and the friction coefficient of PE and PP, but remarkably improved their capability to uptake diclofenac through formation of inclusion complexes with the CDs. Furthermore, the functionalized materials released the drug for 1 h, which could be useful for management of initial pain, inflammation at the insertion site as well as adhesion of certain microorganisms if these materials are used as medicated medical devices.

Stimuli–responsive networks grafted onto polypropylene for the sustained delivery of NSAIDs

Co-polymers of N-isopropyl acrylamide (NIPAAm) and N-(3-aminopropyl) methacrylamide hydrochloride (APMA) were grafted on polypropylene (PP) films by means of a γ-ray pre-irradiation method, with the aim of developing medical devices able to load non-steroidal anti-inflammatory drugs (NSAIDs) and to control their release under physiological conditions. The NIPAAm/APMA molar ratios in the grafts, estimated by Fourier transform infrared attenuated total reflection spectroscopy and X-ray photoelectron spectroscopy analysis, were 4.76 and 1.23 for PP-g-(1M NIPAAm-r-0.5M APMA) and PP-g-(1M NIPAAm-r-1M APMA), respectively. By varying the reaction time, different degrees of grafting were achieved, while the monomer ratio was kept constant. PP-g-(NIPAAm-r-APMA) films showed temperature-responsive swelling, smaller friction coefficients, hemolysis and thrombogenicity and higher cell compatibility, did not elicit secretion of cytokines, and took up remarkable amounts of diclofenac and ibuprofen and sustained delivery for several hours in phosphate buffer, pH 7.4. Coating with carboxymethyl dextran of diclofenac-loaded PP-g-(NIPAAm-r-APMA) films caused a minor discharge of the drug but did not alter the drug release rate.

Biofilm inhibition and drug-eluting properties of novel DMAEMA-modified polyethylene and silicone rubber surfaces

Poly(2-(dimethylaminoethyl) methacrylate) (pDMAEMA) was grafted to low density polyethylene (LDPE) and silicone rubber (SR) in order to make them less susceptible to microbial biofilm formation. The direct grafting of DMAEMA using γ-rays was an efficient and fast procedure for obtaining modified materials, which could be quaternized in a second step using methyl iodide. Raman spectroscopy showed that the grafting occurred only at the surface of the LDPE, but both at the surface and in the bulk of the SR. Consequently, the grafted chains caused changes in the surface-related features of the LDPE (water contact angle and viscoelastic behavior in the dry state) and in the bulk-related properties of the SR (swelling and viscoelasticity in the swollen state). The microbiological assays revealed that the grafted DMAEMA reduced Candida albicans biofilm formation (almost no biofilm on SR), while the quaternized surfaces inhibited C. albicans and Staphylococcus aureus biofilm by more than 99% compared to pristine materials. Modified LDPE and SR were capable of holding considerable amounts of nalidixic acid, an anionic antimicrobial drug, and sustained the release for several hours. In addition, the grafted materials were cytocompatible (fibroblast cell survival > 70%). In conclusion, these materials have the ability to inhibit microbial biofilm formation and at the same time act as drug-eluting systems, and for that reason may hold great promise for anti-biofouling applications.

Acrylic polymer-grafted polypropylene sutures for covalent immobilization or reversible adsorption of vancomycin.

Glycidyl methacrylate (GMA) and acrylic acid (AAc) were separately grafted onto polypropylene (PP) monofilament sutures by means of pre-irradiation using a (60)Co γ-source, with the purpose of loading vancomycin via (i) covalent immobilization through the glycidyl groups of GMA and (ii) ionic interaction with AAc moieties. The effect of absorbed radiation dose, monomer concentration, temperature and reaction time on the grafting degree was evaluated in detail. GMA grafting ranged from 25% to 800% while the grafting yield of AAc onto PP could be tuned between 9% and 454%, at doses from 5 to 50 kGy and a dose rate 13.7 kGy/h. Grafting of GMA or AAc decreased the decomposition temperature and made the sutures swellable to a certain extent. GMA grafting led to a continuous, smooth and thick coating, which was suitable for immobilization of up to 1.9 μg vancomycin per gram. The immobilized vancomycin enabled a reduction in the Staphylococcus aureus CFU adhered to the suture surface. On the other hand, dried AAc-functionalized sutures exhibited a rough and cracked surface which was responsible for a minor increase in the coefficient of friction. PP-g-AAc sutures exhibited pH-dependent swelling and remarkably high capability to host vancomycin (up to 109.9 mg/g), particularly those with an intermediate degree of grafting. Some AAc-functionalized sutures were shown able to inhibit bacterial growth after successive challenges with fresh lawns. Therefore, tuning the yield of grafting of GMA or AAc may enable the preparation of drug-suture combination products that retain or release, respectively, antimicrobial agents.

Radiation grafting of dimethylaminoethylmethacrylate onto poly(propylene).

Radiation-induced grafting of dimethylaminoethylmethacrylate onto poly(propylene) films by preirradiation method in presence of air was investigated. The effects of monomer concentration, preirradiation dose and temperature on grafting value as well as the effect of grafting value on crystallinity of the modified polymer were determined.

Radiation-grafting of 2-bromoethylacrylate onto polyethylene film by preirradiation method

Abstract Radiation-induced graft polymerization of bromoethylacrylate onto a low-density polyethylene (LDPE) film by preirradiaiton method in the presence of air has been investigated. The appropriate reaction conditions for the graft polymerization were determined. It was observed that the grafting is governed by several factors, such as preirradation dose and grafting temperature. The degree of grafting increased rapidly with the initial reaction time and then leveled off to the final value. The optimum temperature for grafting was determined to be 55°C.

Stimuli-responsive polymers for antimicrobial therapy: drug targeting, contact-killing surfaces and competitive release

ABSTRACT Introduction: Polymers can be designed to modify their features as a function of the level and nature of the surrounding microorganisms. Such responsive polymers can endow drug delivery systems and drug-medical device combination products with improved performance against intracellular infections and biofilms. Areas covered: Knowledge on microorganism growth environment outside and inside cells and formation of biofilm communities on biological and synthetic surfaces, together with advances in materials science and drug delivery are prompting strategies with improved efficacy and safety compared to traditional systemic administration of antimicrobial agents. This review deals with antimicrobial strategies that rely on: (i) polymers that disintegrate or undergo phase-transitions in response to changes in enzymes, pH and pO2 associated to microorganism growth; (ii) stimuli-responsive polymers that expose contact-killing groups when microorganisms try to adhere; and (iii) bioinspired polymers that recognize microorganisms for triggered (competitive/affinity-driven) drug release. Expert opinion: Prophylaxis and treatment of infections may benefit from polymers that are responsive to the unique changes that microbial growth causes in the surrounding environment or that even recognize the microorganism itself or its quorum sensing signals. These polymers may offer novel tools for the design of macrophage-, bacteria- and/or biofilm-targeted nanocarriers as well as of medical devices with switchable antibiofouling properties.