DSM Biomedical Materials, Geleen, The Netherlands
The importance of good coverage
Coatings for medical devices have evolved from their primary function, that of providing protective, biocompatible and biomechanical characteristics, to incorporating a variety of pharmacological and biological properties. This evolution is illustrated in the developments in coatings for urological and cardiovascular devices discussed below. However, before addressing the sophisticated additional demands of medical coatings, it is important to recognise that the basic requirements of any coating remain essential. These include wetting, good surface coverage, coating homogeneity, uniform adhesion and resistance to wear.
There are a number of complications in medical devices that are attributable to suboptimal coatings. In the case of lubricious coatings for temporary medical devices such as urological catheters, vascular catheters and guide wires, lubricious properties have been upgraded together with demands for improved wear resistance, hydration times and better, homogeneous surface coverage. This is because poor wear resistance and incomplete hydration can cause delamination of a coating and loss of associated lubricious properties, as well as debris that could elicit a thrombotic response in vascular applications. In urological applications, repeated catheterisation with suboptimal lubricious catheters can lead to urethral irritation, urethral trauma and eventual urinary tract infection (see Figure 1a and 1b).
Lubricious and hydrophilic coatings have been shown to reduce the damage to the mucosal lining,1,2 lead to less haematuria and improve patient comfort.3 Damage to the mucosal lining has been cited as a focus of infections and this has lead to the development of dual functional coatings with a mechanical function of lubricity, and a biological function of antimicrobial activity. These coatings can be useful for urological4 and vascular catheters5 (see Figure 2a and 2b).
In the same way that patients who do not follow a complete regimen of antibiotics can allow bacteria to survive, adapt and thereby develop resistance, it can be argued that incomplete coverage of the catheters with antimicrobial coating can increase the risk of antibiotic resistant strains of bacteria developing at sites of implantation or insertion. Anti-microbial activity has been obtained in a variety of ways, including the use of silver in the form of salts, micro- and nanoparticulate dispersions and in metallised forms.6 Davenas et al. showed clearly how nanoparticulate silver was more effective than silver in a layered metallic coating.7
Figure 1: Coating inhomogeneity is amplified in hydrogel coatings for urological catheters; a: Commercial coating, b: Next generation with a homogeneous coating in the radial direction of the catheter.
One of the earliest reports of an antibiotic coated indwelling catheter was by Sakamoto et al.8 Dibekacin sulphate, an aminoglycoside antibiotic, was used to coat the outside and inner lumen of silicone catheters. The release rate of this drug eluting antibiotic system is governed by the ionic strength of the immersion medium, which in this case was patient derived urine. Clinical in vitro and in vivo studies showed 25- and 13-day release, respectively. Johnson et al. compared a catheter with a coating containing nitrofurazone (NF) with a catheter coated with silver hydrogel.9 This in vitro study involved clinical isolates with an emphasis on multiple drug resistant bacteria. The results indicated that the NF catheter inhibited all bacteria except vancomycin resistant E. Faecium.
Comio et al. used in vitro studies to demonstrate that the immersion of hydrogel and silver coated catheters in antibiotic solution (cefratriaxone and tobramycin) reduced the bacterial adhesion onto silver coated catheters and hydrogel coated catheters.10 Cho reported on a gentamycin releasing coating, which reduced bacterial adhesion in the first 3–5 days after catheter insertion into a rabbit.11
Figure 2: Comparison of commercial samples Com 1 and Com 2 versus a novel
coating with lubricious mechanical function shown by fiction force in Figure 2a, and 30 day antimicrobial activity with a bacterial challenge of 104 colony forming units of various relevant clinical isolates shown in Figure 2b.
(click images to enlarge)
Rifampicin and minocylcine coated catheters have also been shown to be more effective against gram positive bacteria than gram negative bacteria for catheter associated urinary tract infections. This limits their efficacy and furthermore, in parts of the world where these drugs are used to treat tuberculosis, widespread use of rifampicin raises concerns about multiple resistance tuberculosis
It is obviously important that the use of antibiotics in catheters is carefully considered in the context of the worldwide increased incidence of multiple drug resistant bacteria. With regard to further developments in coatings for drug eluting stents, it is the use of pharmacologically active compounds in antimicrobial coatings that has in part paved the way for advances in this area.
Drug eluting stent coatings
Drug eluting stent coatings (DES) were originally developed with the aim of reducing in stent restenosis, neointimal proliferation and the inflammation and thrombus formation associated with the use of bare metal stents. Their short term performance has had a significant impact on interventional cardiology. Numerous nondegradable polymers such as polyparacyclophanes, polyacrylates, polyethers, polyurethanes, acrylate-vinylacetate copolymers, styrenics, fluoropolymers and methacrylated phosphorylcholine have been evaluated for their potential use as coating matrices for drug eluting stents.13 These polymers were evaluated with a range of anti-inflammatory and anti-proliferative drugs such as rapamycin, paclitaxel, dexamethasone and the limus family of drugs. Research and clinical trials finally led to three initial polymer coating systems becoming the forerunner coating materials in DES. These were poly(n butylmethacrylate)co poly(ethylenevinylacetate) copolymer containing 33% sirolimus with a polybutylmethacrylate top coat to control release,14 polystyrene isobutylene styrene triblock copolymer with paclitaxel,15 and polyurethane coating with dexamethasone.16
Current experience with DES confirms the short term benefits of DES coatings. However, long term complications such as restenosis, late stent thrombosis and hypersensitivity of some patients to the polymeric coatings remain an issue. At the recent Transcatheter Cardiovascular Therapeutics 2007 conference,17 Baim highlighted a number of factors that could be directly or indirectly attributed to the coating material.18 These, in order of decreasing importance are
- delayed endothelialisation
- exposed stent struts (once again emphasising the importance of complete coating coverage)
- inflammatory polymer on stent
- incomplete drug elution
- suboptimal drug elution rate.
The findings summarised above have triggered the evolution of the next generation of coatings. Two noteworthy advances are the development of biodegradable and cell signalling coatings.
Biodegradable DES coatings
Biodegradable coatings may address some of the complications such as inflammation, late stent thrombosis and hypersensitivity attributable to the persistence of a coating on the stent. Research into biodegradable polymer coatings for DES has involved the biodegradable polymers, polylactic acid and polylactide-co-glycolide (PLGA). PLGA was loaded with paclitaxel and was used as a coating reservoir in holes on a stent.19 Poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) coatings bearing rapamycin and paclitaxel were tailored to release drugs for several months.20
Preliminary clinical evidence with Everolimus eluting biodegradable coating has indicated that it is a safe method to reduce neointimal hyperplasia and restenosis. To date, there are number of DES with biodegradable coatings that have a CE mark and are undergoing preclinical or clinical trials. These stents include Biomatrix,21 Costar,22 and Infinnium.23
Cell signalling DES coatings
Figure 3: Confocal images of S. epidermidis biofilm dispersal by DispersinB.
The problem of delayed endothelialisation and smooth muscle cell proliferation of drug eluting stents has also led to the development of coatings with bioactive surfaces that can accelerate or suppress cellular proliferation. BiodivYsio DES (Biocompatibles Ltd, www.biocompatibles.com) uses a polymer based on methacrylated phosporylcholine loaded with phVEGF 2-Plasmid, which contains the deoxyribonucleic acid code for a vascular endothelial growth factor that has been shown to encourage re-endothelialisation in a rabbit model.24
Figure 4: The effect of Dispersin B (12.5 µg/mL) on E. coli and gram-positive bacteria such as S. epidermidis, S.aureus, and Coagulase-negative staphylococci (CoNS-42) were diluted to 5% in colony forming antigen medium and tryptic soy broth.
(click image to enlarge)
Integrin binding peptides such as cyclic arginine-glycine-aspartic acid incorporated into a coating have been tested to encourage endothelialisation by the recruitment of endothelial progenitor cells in porcine coronary arteries.25 Cell signalling that suppresses cellular activity, for example, the use of cytochalasin D in polybutylmethacrylate-co-polyvinyl acetate stents, has been reported to reduce smooth muscle cell proliferation and migration in a porcine coronary artery.26
Thus, increasingly sophisticated molecules, beginning with small molecules up to biologics (peptides, oligonucleotides and complete functional proteins) are being incorporated into coatings for medical devices as demands become more complex. Medical coatings are evolving to selectively encourage or discourage cellular proliferation.
Clever yet effective coatings
Further evidence of the increasing sophistication of coatings is the report at the Biointerface 2007 conference of an enzyme (Dispersin B) bearing coating that disperses biofilms by cleaving the ß-1,6 glycosidic bonds in bacterial biofilms; this is a coating solution to address catheter associated infections (see Figures 3 and 4).27,28
The potential impact of coatings with complex biological functionality is exciting. However, optimism should be tempered with the sober recognition that the basic characteristics of coatings such as complete surface coverage, adhesion and wear resistance are important to achieving effective and robust medical coatings. Coating failure may dominate the advanced biological attributes introduced into a coating.
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13. J. Jagur-Grodzinski, Polym. Adv. Technol., 17, 395–418 (2006).
14. Cyper stent, Cordis, Johnson and Johnson (www.cypherusa.com).
15. Taxus stent, Boston Scientific Corp (www.taxus-stent.com).
16. Dexamet stent, Abbot Labs (www.abbottvascular.com).
17. Transcatheter Cardiovascular Therapeutics Conference 2007, October 2025 Washington District of Columbia, USA (www.tct2007.com).
18. D.S. Baim, “Modalities to Minimise Polymer Toxicity: Abluminal Coatings, Bioabsorbable Polymers and More,” Boston Scientific Corp. Lecture, TCT Transcatheter Cardiovascular Therepeutics Conference, October 2007, Washington, District of Columbia, USA (www.tct2007.com).
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20. F. Alexis, S.S. Venkatraman, J. Control. Release, 98, 67–74 (2004).
21. Biomatrix stent, Biosensors International (www.biosensorsintl.com).
22. Costar stent, Conor Medsystems (J&J) (www.conormed.com).
23. Infinnium stent, Sahajanand Medical Technologies (www.smtpl.com/index.html).
24. D.H. Walter, D.W. Losordo, Circulation, 110, 36–45 (2004).
25. R. Blindt et al., Intervent. Cardiol. 47, 9, 1786–1795 (2006).
26. K.J. Salu et. al., Cardiovasc. Res., 69, 536–544 (2006).
27. S. Madyastha, G. Froehlich, “Synergistic Anti-Biofilm Antimicrobial Compositions for Medical and Industrial Applications,” Kane Biotech Presentation, BioInterface 2007, San Mateo California, USA (www.surfaces.org).
28. J.B. Kaplan et. al., Antimicrob. Agents and Chemotherapy, 48, 7, 2633 (2004).
Aylvin A. Dias, Ph.D., is Research and Development Manager, Materials Chemistry and Technology, at DSM Biomedical Materials, PO Box 18, NL-6160 MD, Geleen, The Netherlands, tel. +31 464 761 067, e-mail: email@example.com, www.dsmbiomedical.com.