Sustained release of antibiotic from polyurethane coated implant materials

Implant associated infections are of increasing importance. To minimize the risks of implant-associated infections recent biomedical strategies have led to the modification of the medical device surfaces. The modifications are in the terms of increasing surface biocompatibility and decreasing bacterial adherence, which can be achieved by applying a coating of biocompatible polymer onto the said surfaces. Entrapping anti-infective agents in a polymer matrix provides an approach to kill bacteria and combat the possibility of any residual infection. We have prepared a biodegradable polyester urethane coat for implant materials, which have the property to accommodate antibiotics within itself. These polyurethane coating materials were characterized by FTIR spectroscopy, swelling property in SBF, gravimetric analysis, drug release, and biocompatibility study. Drug release rates, bacterial colonization and morphological features were also evaluated to predict and understand the antimicrobial activity of these delivery systems. Drug release characteristics were investigated and the physico-chemical mechanisms of the delivery were discussed. Results suggest that the polyester urethane can be used as an implant coating material and can be used as a matrix for the sustained delivery of anti-infective agent.     

Effect of the solubility of antibiotics on their release from degradable polyurethane

Application of biodegradable polyester urethane, as a drug loading matrix in the form of a coating on implant devices was investigated. Polyester urethane films were loaded with model antibiotics, like rifampicin, gentamicin and ciprofloxacin and their release characteristics were evaluated in simulated body fluid. Effect of solubility of antibiotics and degradation of matrix on the drug release behavior of biodegradable polyester urethane coating was also studied. It was observed that antibiotics having hydrophilicity or lipophilicity same as that of polymer matrix provide an extended release with relatively less initial burst release. Effect of degradation of polymer matrix has a dual significance in this case and the drug release rate increases with the increase in degradation rate. A high initial burst release was observed for antibiotics having hydrophilicity or lipophilicity opposite to that of polyurethane matrix and hence in this case antibiotic release was not significantly controlled by degradation of matrix.     

Recent advances in hydrogel-based anti-infective coatings

Bacterial infections associated with biomedical devices and implants have posed a great challenge to global healthcare systems.These infections are mainly caused by bacterial biofilm formed on the surface of biomaterials,protecting the encapsulated bacteria from conventional antibiotic treatment and attack of the immune system.As the bacterial biofilm is difficult to eradicate,bactericidal and antifouling coatings have emerged as promising strategies to prevent biofilm formation and subsequent infections.Hydrogels with three-dimensional crosslinked hydrophilic networks,tunable mechanical property and large drug-loading capacity are desirable coating materials,which can kill bacteria and/or prevent bacterial adhesion on the surface,inhibiting biofilm formation.Herein,we review recent developments of hydrogels as anti-infective coatings.Particularly,we highlight two chemical approaches(graft-from and graft-to),which have been used to immobilize hydrogels on surfaces,and present advances in the development of bactericidal(contact-killing and antimicrobial-releasing),antifouling(hydrophilic polymer network)and bifunctional hydrogel coatings with both bactericidal and antifouling activities.In addition,the challenges of hydrogel coatings for clinical applications are discussed,and future research directions of anti-infective hydrogel coatings are proposed.     

Protein Adhesion at Poly(ethylene glycol) Modified Surfaces

The inhibition of protein adsorption to the surfaces of biomedical devices is a crucial requirement for avoiding implant‐associated infections or thrombus formation on blood‐contacting artificial surfaces and thus for increasing the long‐term biocompatibility of the devices. Here, the use of surface plasmon resonance and scanning force microscopy using protein‐modified tips (see figure) to study protein adhesion on poly(ethylene glycol) (PEG) grafted polymer materials is discussed. The PEG‐rafted materials are revealed to have significantly reduced affinity to proteins.     

Resorbable Antibiotic Coatings for Bone Substitutes and Implantable Devices

Antibiotic delivery systems based on biodegradable coatings have found considerable interest for the prophylaxis and local therapy of biomaterial‐related infections. In this study sparingly water‐soluble gentamicin salts have been prepared and tested as biodegradable antibiotic‐releasing coating systems. Using the coating systems, homogeneous, well adhering films can be produced on various implant materials, like ceramics, glasses or metals surfaces, with different surface morphologies. The in vitro release profiles of the antibiotic coating systems were characterized by an initial burst release followed by a sustained release of small antibiotic amounts up to several weeks. It was found that the in vitro release, especially in the initial phase, can be modulated by the ratio between highly water‐soluble gentamicin salts and sparingly soluble ones in the coating. Coating systems of the same type as described for gentamicin are available from a wide range of antibiotics differing in structure and mechanism of antibacterial action. Based on these results, the developed antibiotic coatings offer new perspectives to prevent and treat biomaterial‐related infections.     

Characterization of silicone pressure-sensitive adhesive episcleral implant for drug delivery

The development of an effective sustained ocular drug delivery system remains a challenging task. The objective of the present study was to characterize a silicone pressure sensitive adhesive (PSA) episcleral implant system for transscleral drug delivery. Silicone PSA implants for dexamethasone, atenolol, and bovine serum albumin (BSA) were prepared at different polymer-to-drug mass ratios. Implant adhesion to human cadaver sclera was measured. Drug release experiments were conducted in well-stirred containers in vitro. The results were then analyzed using a pharmacokinetic model and in vitro–in vivo data comparison from previous studies. The silicone PSA episcleral implants in the present study had an average diameter of 3.5?mm and a thickness of 0.8?mm. Drug release from the silicone PSA implants was influenced by drug solubility, implant polymer content, and implant coating. Drug release from the implants was observed to follow the receding boundary release mechanism and was solubility dependent with the higher water solubility drug showing higher release rate than the low-solubility drug. Increasing polymer content in the implants led to a significant decrease in the drug release rate. Coated implants reduced the initial burst effect and provided lower release rates than the uncoated implants. These implants provided sustained drug release that could last up to several months in vitro and demonstrated the potential to offer drug delivery for chronic ocular diseases via the transscleral route.     

Novel fatty acid gentamicin salts as slow-release drug carrier systems for anti-infective protection of vascular biomaterials

Infections of vascular prostheses are still a major risk in surgery. The current work presents an in vitro evaluation of novel slow release antibiotic coatings based on new gentamicin fatty acid salts for polytetrafluoroethylene grafts. These grafts were coated with gentamicin sodium dodecyl sulfate, gentamicin laurate and gentamicin palmitate. Drug release kinetics, anti-infective characteristics, biocompatibility and haemocompatibility of developed coatings were compared to commercially available gelatin sealed PTFE grafts (SEALPTFE?) and knitted silver coated Dacron(?) grafts (InterGard(?)). Each gentamicin fatty acid coating showed a continuous drug release in the first eight hours followed by a low continuous release. Grafts coated with gentamicin fatty acids reduced bacterial growth even beyond pathologically relevant high concentrations. Cytotoxicity levels depending on drug formulation bringing up gentamicin palmitate as the most promising biocompatible coating. Thrombelastography studies, ELISA assays and an amidolytic substrate assay confirmed haemocompatibility of developed gentamicin fatty acid coatings comparable to commercially available grafts.     

Rapid inactivation of multidrug-resistant bacteria and enhancement of osteoinduction via titania nanotubes grafted with polyguanidines

The rapid in situ inhibition of bacterial contamination and subsequent infection without inducing drug resistance is highly vital for the successful implantation and long-term service of titanium(Ti)-based orthopedic implants. However, the instability and potential cytotoxicity of current coatings have deterred their clinical practice. In this study, anodic oxidized titania nanotubes(TNT) were modified with antibacterial polyhexamethylene guanidine(PG) with the assistance of 3,4-dihydroxyphenylacetic acid. Interestingly, the prepared TNT-PG coating exhibited superior in vitro antibacterial activity than flat Ti-PG coating and effectively killed typical pathogens such as Escherichia coli and superbug methicillinresistant Staphylococcus aureus with above 4-log reduction( 99.99 % killed) in only 5 min. TNT-PG coating also exerted excellent hemocompatibility with red blood cells and nontoxicity toward mouse pre-osteoblasts(MC3 T3-E1) in 1 week of coculture. In addition, the efficient in vivo anti-infective property of this coating was observed in a rat subcutaneous infection model. More importantly, TNT-PG coating improved the expression of alkaline phosphatase and enhanced the extracellular matrix mineralization of pre-osteoblasts, denoting its osteoinductive capacity. This versatile TNT-PG coating with excellent antibacterial activity and biocompatibility could be a promising candidate for advanced orthopedic implant applications.     

Transdermal Delivery Devices: Fabrication,Mechanics and Drug Release from Silk

Microneedles are a relatively simple, minimally invasive and painless approach to deliver drugs across the skin. However, there remain limitations with this approach because of the materials most commonly utilized for such systems. Silk protein, with tunable and biocompatibility properties, is a useful biomaterial to overcome the current limitations with microneedles. Silk devices preserve drug activity, offer superior mechanical properties and biocompatibility, can be tuned for biodegradability, and can be processed under aqueous, benign conditions. In the present work, the fabrication of dense microneedle arrays from silk with different drug release kinetics is reported. The mechanical properties of the microneedle patches are tuned by post‐fabrication treatments or by loading the needles with silk microparticles, to increase capacity and mechanical strength. Drug release is further enhanced by the encapsulation of the drugs in the silk matrix and coating with a thin dissolvable drug layer. The microneedles are used on human cadaver skin and drugs are delivered successfully. The various attributes demonstrated suggest that silk‐based microneedle devices can provide significant benefit as a platform material for transdermal drug delivery.     

Bactericidal property and biocompatibility of gentamicin-loaded mesoporous carbonated hydroxyapatite microspheres

Implant-associated infection is a serious problem in orthopaedic surgery. One of the most effective ways is to introduce a controlled antibiotics delivery system into the bone filling materials, achieving sustained release of antibiotics in the local sites of bone defects. In the present work, mesoporous carbonated hydroxyapatite microspheres (MCHMs) loaded with gentamicin have been fabricated according to the following stages: (i) the preparation of the MCHMs by hydrothermal method using calcium carbonate microspheres as sacrificial templates, and (ii) loading gentamicin into the MCHMs. The MCHMs exhibit the 3D hierarchical nanostructures constructed by nanoplates as building blocks with mesopores and macropores, which make them have the higher drug loading efficiency of 70–75% than the conventional hydroxyapatite particles (HAPs) of 20–25%. The gentamicin-loaded MCHMs display the sustained drug release property, and the controlled release of gentamicin can minimize significantly bacterial adhesion and prevent biofilm formation against S. epidermidis. The biocompatibility tests by using human bone marrow stromal cells (hBMSCs) as cell models indicate that the gentamicin-loaded MCHMs have as excellent biocompatibility as the HAPs, and the dose of the released gentamicin from the MCHMs has no toxic effects on the hBMSCs. Hence, the gentamicin-loaded MCHMs can be served as a simple, non-toxic and controlled drug delivery system to treat bone infections.     

Evaluation of the biocompatibility of a new vascular prosthesis coating by detection of prosthesis-specific antibodies

In recent experimental studies, we could demonstrate the occurrence of antibodies against the prosthesis matrix and coating following implantation of polyester-based vascular grafts. Therefore, this study aimed at evaluating the biocompatibility of a new absorbable polymer coating by detection of antibodies against the coating and the polyester matrix. Two polyester vascular prostheses coated either with the polymer (PP-prosthesis) or with gelatine (PG-prosthesis) were functionally implanted into sheep (n = 22 per group). Blood was drawn on days 1 (pre-OP) and 7, 14, 28, 56, 84, 140 (post-OP). Homogenates from both prostheses (PP-target or PG-target) or from an uncoated prosthesis (P-target) were used as assay targets in a particle-based immunoassay. The antibody binding against the P-target was significantly higher in the PP-group than in the PG-group on days 7–56, but not on days 84 and 140. Within both groups, no significant differences but a significant correlation between the binding against the P-target and the coated target was found. Therefore, the absorbable polymer did not induce a specific humoral immune response. In conclusion, the overall immunogenicity of the polymer-coated graft was comparable to the gelatine-coated graft. The detection of prosthesis-specific antibodies seems to be useful for in vivo biocompatibility testing.     

Promoting Bone Mesenchymal Stem Cells and Inhibiting Bacterial Adhesion of Acid-Etched Nanostructured Titanium by Ultraviolet Functionalization

Titanium(Ti) and its alloys are used extensively in orthopedic implants because of their excellent biocompatibility,mechanical properties and corrosion resistance. However,titanium-based implant materials face many severe complications,such as implant loosening due to poor osseointegration and bacterial infections,which may lead to implant failure. Hence,preparing a biomaterial surface,which enhances the interactions with host cells and inhibits bacterial adhesion,may be an optimal strategy to reduce the incidence of implant failure. This study aims to improve osseointegration and confer antibacterial properties on Ti through a combination of two surface modifications including nanostructuring generated by acid etching and ultraviolet(UV) light treatment.Our results showed that without UV treatment,the acid etching treatment of Ti surface was effective at both improving the adhesion of bone mesenchymal stem cells(BMSCs) and increasing bacterial adhesion. A further UV treatment of the acid-etched surface however,not only significantly improved the cell adhesion but also inhibited bacterial adhesion. The acid-etched nanostructured titanium with UV treatment also showed a significant enhancement on cell proliferation,alkaline phosphatase(ALP) activity and mineralization. These results suggest that such nanostructured materials with UV treatment can be expected to have a good potential in orthopedic applications.     

In vitro drug release study of methacrylate polymer blend system: effect of polymer blend composition,drug loading and solubilizing surfactants on drug release

The application of polymers as the drug delivery systems for treating oral infections is a relatively new area of research. The present study was to test the release of the antibacterial drug chlorhexidine diacetate (CHDA), the antifungal drug Nystatin (NYS) and the antiviral drug acyclovir (ACY) from polymer blends of poly(ethyl methacrylate) and poly(n-hexyl methacrylate) of different compositions. The effects of polymer blend composition, drug loading and solubilizing surfactants on the release of the drugs have been studied. Measurements of the in vitro rate of drug release showed a sustained release of drug over extended periods of time. Drug release rates decreased with increasing PEMA content in polymer blends. CHDA release rates increased steadily with increasing drug load. The drug release rates increased with the addition of surfactants. This study demonstrates that the three therapeutic agents show a sustained rate of drug release from polymer blends of PEMA and PHMA over extended periods of time. By varying polymer blend compositions as well as the drug concentration (loading), it is possible to control the drug release rates to a desired value. The drug release rate is enhanced by addition of surfactants that solubilize drugs in the polymer blends.     

用细菌粘附法比较TC4钛合金及其表面改性后的抗菌能力

对牙种植体用材料TC4(Ti6A14V)进行不同工艺的表面改性处理.应用细菌粘附方法,在荧光显微镜下直接计数,观察未处理试样和不同工艺处理后试样表面的细菌粘附,以评价改性表面的抗菌能力;同时采用SPSS统计软件分析对比两种工艺处理后改性表面的抗菌能力.细菌粘附和统计结果显示,未处理试样表面粘附了大量细菌;处理后试样表面粘附数量已显著减少;两种处理工艺改性后的表面之间细菌粘附量的差别没有统计学差异,即两种工艺处理后的改性表面的抗菌能力没有显著的差异.     

Development of a specially tailored local drug delivery system for the prevention of fibrosis after insertion of cochlear implants into the inner ear

A cochlear implant (CI)-associated local drug delivery system based on dexamethasone (DMS) was developed with the purpose to inhibit the growth of fibrotic tissue which influences the signal transmission from the CI to the neurons of the inner ear. For the realization of a targeted DMS delivery the following concepts were combined: modification of the silicone-based electrode carrier by incorporation of DMS and a DMS-containing polymeric coating chemically attached on the surface of the electrode carrier. It was demonstrated that the coated CI showed a high coating stability in a simulated implantation procedure. The in vitro drug release studies in a quasi-stationary model revealed a faster DMS release in the initial phase originating from the DMS-containing coatings and then a lower and sustained DMS release originating from the DMS-loaded silicone carrier. The performed in vitro biocompatibility study confirmed that the released DMS was non-toxic for cultured spiral ganglion cells.     

Resistant starch as a carrier for oral colon-targeting drug matrix system

In this study, a novel tablet of protein drug matrix for colon targeting was developed using resistant starch as a carrier prepared by pre-gelatinization and cross-linking of starch. The effects of pre-gelatinization and cross-linking on the swelling and enzymatic degradation of maize starch as well as the release rate of drug from the matrix tablets were examined. Cross-linked pre-gelatinized maize starches were prepared by double modification of pre-gelatinization and cross-linked with POCl₃, and bovine serum albumin was used as a model drug. For in vitro drug release assays, the resistant starch matrix tablets were incubated in simulated gastric fluid, simulated intestinal fluid and simulated colonic fluid, respectively. The content of resistant starch and swelling property of maize starch were increased by pre-gelatinization and cross-linking, which retarded its enzymatic degradation. Drug release studies have shown that the matrix tablets of cross-linked pre-gelatinized maize starch could delivery the drug to the colon. These results indicate that the resistant starch carrier prepared by pre-gelatinization and cross-linking can be used for a potential drug delivery carrier for colon-targeting drug matrix delivery system.     

Surface Engineering of Biodegradable Magnesium Alloys for Enhanced Orthopedic Implants

Magnesium (Mg) alloys have been promised for biomedical implants in orthopedic field, however, the fast corrosion rate and mode challenge their clinical application. To push Mg alloys materials into practice, a composite coating with biodegradable and high compatible components to improve anticorrosion property of an Mg alloy (i.e., AZ31) is designed and fabricated. The inner layer is micro‐nano structured Mg(OH)₂ through hydrothermal treatment. Then stearic acid (SA) is introduced to modify Mg(OH)₂ for better reducing the gap below a surface‐degradation polymer layer of poly(1,3‐trimethylene carbonate). Benefited by the SA modification effect, this sandwiched coating avoids corrosive medium penetration via enhancing the adhesion strength at the interface between outer and inner layers. Both in vitro and in vivo tests indicate that the composite coating modified AZ31 perform a better anticorrosion behavior and biocompatibility compared to bare AZ31. Strikingly, a 1.7‐fold improvement in volume of newly formed bone is observed surrounding the composite coating modified implant after 12 week implantation. The sandwiched biocompatible coating strategy paves a hopeful way for future translational application of Mg alloys orthopedic materials in clinics.     

Osteoblast behaviour on in situ photopolymerizable three-dimensional scaffolds based on D, L-lactide, ε-caprolactone and trimethylene carbonate

Polymer networks formed by photocrosslinking of multifunctional oligomers have great potential as injectable and in situ forming materials for bone tissue engineering. Porous scaffolds varying in polyester type and crosslinking density were prepared from methacrylate-endcapped oligomers based on D,L-lactide, ε -caprolactone and trimethylene carbonate: LA/CL-hexanediol, LA/CL-dipentaerythritol and LA/TMC-HXD. The biocompatibility and bone formation were related with the degradation time and mechanical properties. The viability of fibroblasts was evaluated after incubation with extraction medium by MTT-assay. All scaffolds showed a good biocompatibility. Rat bone marrow cells were cultured on the scaffolds for 21 days and were able to attach and differentiate on the scaffolds. The cells expressed high alkaline phosphatase activity, have formed a mineralized extracellular matrix and secreted osteocalcin. TEM of the polymer interface revealed osteoblasts which secreted an extracellular matrix containing matrix vesicles loaded with apatite crystals. LA/TMC-HXD, LA/CL-HXD and LA/CL-DPENT had a 50% mass loss at 3,5 months respectively 6 and 7, 5 months. The mechanical properties improve by increasing the branching of the precursor methacrylates (by replacing HXD by DPENT) but do not depend on their chemical composition. Hence, scaffolds with high elastic properties and variable degradation time can be obtained, which are promising for bone tissue engineering. Author to whom all correspondence should be addressed.     

Biological properties of vascular substitutes based on an original collagenic coating

To enlarge the field of application for polyester vascular prostheses in order to restore small-diameter vessels, original collagenic-based composites have been developed in our laboratory. The polyester knit of standard prostheses has been modified by radiochemical grafting of the Type I collagen-based matrix. In order to check the properties of this new coating, biological tests have been carried out. We noticed that on modified surfaces: fibrinogen adsorption is less important than albumin adsorption; only 50% platelets interact actively with the modified material in comparison with the other materials; the coating is more resistant to enzymatic degradation; and there is partial denaturation of the collagen but this collagen is still specifically recognized by Type I collagen antibody.     

Inorganic materials as drug delivery systems in coronary artery stenting

Recent studies proved coronary stent implantation to be superior over conventional angioplasty in the treatment of coronary artery disease. However, restenosis remains one of the most crucial problems in interventional cardiology. Inflammatory infiltrates and foreign body reactions can be found in the tissue surrounding the struts in stenting. Thrombogenesis, proliferation of α‐actin expressing cells (smooth muscle cells) and hyperplasia of the intima occur. In order to improve the biocompatibility of the stents, new stent designs and stent coatings have been developed. One advantage of stent coating is the combination of mechanical stability of the stent with the biocompatibility of the coating. The coatings are divided into active and passive coatings. Passive coatings improve the biocompatibility of the stent, while active coatings may suppress neointima proliferation by releasing anti‐inflammatory or antiproliferative substances. Immunosuppressive drugs (tacrolimus, sirolimus) and cytostatic drugs (paclitaxel) have been tested in several studies and showed promising results. However, it could also be demonstrated that polymer‐coated stents used as a matrix for drug release reduced the hyperplasia of the intima. However, after dissipation of the immunosuppressants or cytostatics, the presence of the polymer itself lead to a delayed inflammation and proliferation causing restenosis. Thus, efforts have been made to develop inorganic coatings that are suitable for drug loading. One promising approach is a new nanoporous alumina coating. Preliminary tests with this coating revealed favourable loading characteristics and sustained drug release in vivo. The present article provides an overview on different approaches for stent coatings.