Startseite Implant-associated local drug delivery systems based on biodegradable polymers: customized designs for different medical applications
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Implant-associated local drug delivery systems based on biodegradable polymers: customized designs for different medical applications

  • Katrin Sternberg EMAIL logo , Svea Petersen , Niels Grabow , Volkmar Senz , Henriette Meyer zu Schwabedissen , Heyo K. Kroemer und Klaus-Peter Schmitz
Veröffentlicht/Copyright: 12. Juni 2013
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Abstract

Implants providing controlled, local release of active substances are of interest in different medical applications. Therefore, the focus of the present article is the development of implant-associated diffusion- or chemically controlled local drug delivery (LDD) systems based on biodegradable polymeric drug carriers. In this context, we provide new data and review our own recently published data concerning the drug release behavior of diffusion-controlled LDD systems in relation to the kind of polymer, drug content, coating mass/thickness, and layer composition. We demonstrate that polymers allow a wide range of control over the drug release characteristics. In this regard, we show that the glass transition temperature of a polymer has an impact on its drug release. Additionally, the blending of hydrophobic, semicrystalline polymers with amorphous polymers leads to an increase in the rate of drug release compared with the pure semicrystalline polymer. Moreover, the percentage loading of the embedded drug has a considerable effect on the rate and duration of drug release. Furthermore, we discuss chemically controlled LDD systems designed for the release of biomolecules, such as growth factors, as well as nanoparticle-mediated LDD systems. With our own published data on drug-eluting stents, microstents, and cochlear implants, we highlight exemplary implant-associated LDD systems designed to improve implant performance through the reduction of undesirable effects such as in-stent restenosis and fibrosis.


Corresponding author: Prof. Dr. Katrin Sternberg, Institute for Biomedical Engineering, University of Rostock, Friedrich-Barnewitz-Straße 4, 18119 Rostock, Germany, E-mail:

The authors would like to thank Thomas Langer, Thomas Reske, Daniela Arbeiter, Peter Littwin, Martina Schröder, and Andrea Rohde for their technical assistance. Furthermore, the Tepha Inc. (Lexington, MA, USA) is acknowledged for the supply of the polymeric biomaterial P(4HB), especially David Martin for his helpful suggestions. Parts of this work were funded by the Deutsche Forschungsgemeinschaft (DFG) within SFB Transregio 37 “Mikro- und Nanosysteme in der Medizin – Rekonstruktion biologischer Funktionen” (GZ: TRR 37) and the Bundesministerium für Bildung und Forschung (BMBF) within REMEDIS “Höhere Lebensqualität durch neuartige Mikroimplantate” (FKZ: 03IS2081).

References

[1] Acharya G, Park K. Mechanisms of controlled drug release from drug-eluting stents. Adv Drug Deliv Rev 2006; 58: 387–401.10.1016/j.addr.2006.01.016Suche in Google Scholar

[2] Alexis F. Factors affecting the degradation and drug-release mechanism of poly(lactic acid) and poly[(lactic acid)-co-(glycolic acid)]. Polym Int 2005; 54: 36–46.10.1002/pi.1697Suche in Google Scholar

[3] Andreopoulos AG. Plasticization of biodegradable polymers for use in controlled release. Clin Mater 1994; 15: 89–92.10.1016/0267-6605(94)90074-4Suche in Google Scholar

[4] Banai S, Chorny M, Gertz SD, et al. Locally delivered nanoencapsulated Tyrphostin (AGL-2043) reduces neointima formation in balloon-injured rat carotid and stented porcine coronary arteries. Biomaterials 2005; 26: 451–461.10.1016/j.biomaterials.2004.02.040Suche in Google Scholar

[5] Bangham AD. Liposomes: the Babraham connection. Chem Phys Lipids 1993; 64: 275–285.10.1016/0009-3084(93)90071-ASuche in Google Scholar

[6] Bhargava B, Reddy NK, Karthikeyan G, et al. A novel paclitaxel-eluting porous carbon-carbon nanoparticle coated, nonpolymeric cobalt-chromium stent: evaluation in a porcine model. Catheter Cardiovasc Interv 2006; 67: 698–702.10.1002/ccd.20698Suche in Google Scholar PubMed

[7] Bohl A, Rohm HW, Ceschi P, et al. Development of a specially tailored local drug delivery system for the prevention of fibrosis after insertion of cochlear implants into the inner ear. J Mater Sci Mater Med 2012; 23: 2151–2162.10.1007/s10856-012-4698-zSuche in Google Scholar PubMed

[8] Bünger CM, Grabow N, Kröger C, et al. Iliac anastomotic stenting with a sirolimus-eluting biodegradable poly-L-lactide stent: a preliminary study after 6 weeks. J Endovasc Ther 2006; 13: 630–639.10.1583/06-1899R.1Suche in Google Scholar PubMed

[9] Bünger CM, Grabow N, Sternberg K, et al. Sirolimus-eluting biodegradable poly-L-lactide stent for peripheral vascular application: a preliminary study in porcine carotid arteries. J Surg Res 2007; 139: 77–82.10.1016/j.jss.2006.07.035Suche in Google Scholar PubMed

[10] Cen D, Gonzalez RI, Buckmeier JA, Kahlon RS, Tohidian NB, Meyskens FL Jr. Disulfiram induces apoptosis in human melanoma cells: a redox-related process. Mol Cancer Ther 2002; 1: 197–204.Suche in Google Scholar

[11] Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med 1994; 331: 496–501.10.1056/NEJM199408253310802Suche in Google Scholar PubMed

[12] Freier T, Kunze C, Nischan C, et al. In vitro and in vivo degradation studies for development of a biodegradable patch based on poly(3-hydroxybutyrate). Biomaterials 2002; 23: 2649–2657.10.1016/S0142-9612(01)00405-7Suche in Google Scholar

[13] Garg S, Serruys PW. Coronary stents: current status. J Am Coll Cardiol 2010; 56: S1–S42.10.1016/j.jacc.2010.06.007Suche in Google Scholar PubMed

[14] Garg S, Serruys PW. Coronary stents: looking forward. J Am Coll Cardiol 2010; 56: S43–S78.10.1016/j.jacc.2010.06.008Suche in Google Scholar PubMed

[15] Goddard JM, Hotchkiss JH. Polymer surface modification for the attachment of bioactive compounds. Prog Polym Sci 2007; 32: 698–725.10.1016/j.progpolymsci.2007.04.002Suche in Google Scholar

[16] Grabow N, Martin DP, Schmitz K-P, Sternberg K. Absorbable polymer stent technologies for vascular regeneration. J Chem Technol Biotechnol 2010; 85: 744–751.10.1002/jctb.2282Suche in Google Scholar

[17] Grabow N, Schlun M, Sternberg K, Hakansson N, Kramer S, Schmitz K-P. Mechanical properties of laser cut poly(L-lactide) micro-specimens: implications for stent design, manufacture, and sterilization. J Biomech Eng 2005; 127: 25–31.10.1115/1.1835349Suche in Google Scholar PubMed

[18] Grüntzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med 1979; 301: 61–68.10.1056/NEJM197907123010201Suche in Google Scholar PubMed

[19] Gümüşderelioglu M, Deniz G. Sustained release of mitomycin-C from poly(DL-lactide)/poly(DL-lactide-co-glycolide) films. J Biomater Sci Polym Ed 2000; 11: 1039–1050.10.1163/156856200743562Suche in Google Scholar PubMed

[20] Hargunani CA, Kempton JB, DeGagne JM, Trune DR. Intratympanic injection of dexamethasone: time course of inner ear distribution and conversion to its active form. Otol Neurotol 2006; 27: 564–569.Suche in Google Scholar

[21] Hawkins MJ, Soon-Shiong P, Desai N. Protein nanoparticles as drug carriers in clinical medicine. Adv Drug Deliv Rev 2008; 60: 876–885.10.1016/j.addr.2007.08.044Suche in Google Scholar PubMed

[22] Jedlinski Z, Kowalczuk M, Glowkowski W, Grobelny J, Szwarc M. Novel polymerization of b-butyrolactone initiated by potassium naphthalenide in the presence of a crown ether or a cryptand. Macromolecules 1991; 24: 349–352.10.1021/ma00002a002Suche in Google Scholar

[23] Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006; 48: 193–202.10.1016/j.jacc.2006.03.042Suche in Google Scholar

[24] Kim SH, Jeong JH, Chun KW, Park TG. Target-specific cellular uptake of PLGA nanoparticles coated with poly(L-lysine)-poly(ethylene glycol)-folate conjugate. Langmuir 2005; 21: 8852–8857.10.1021/la0502084Suche in Google Scholar

[25] Kirtane AJ, Gupta A, Iyengar S, et al. Safety and efficacy of drug-eluting and bare metal stents: comprehensive meta-analysis of randomized trials and observational studies. Circulation 2009; 119: 3198–3206.10.1161/CIRCULATIONAHA.108.826479Suche in Google Scholar

[26] Kober T, König I, Weber M, Kojda G. Diethyldithiocarbamate inhibits the catalytic activity of xanthine oxidase. FEBS Lett 2003; 551: 99–103.10.1016/S0014-5793(03)00876-7Suche in Google Scholar

[27] Lanzer P, Sternberg K, Schmitz KP, Kolodgie F, Nakazawa G, Virmani R. Drug-eluting coronary stent very late thrombosis revisited. Herz 2008; 33: 334–342.10.1007/s00059-008-3080-xSuche in Google Scholar

[28] Lendlein A. Polymere als Implantatwerkstoffe. Chem Unserer Zeit 1999; 33: 279–295.10.1002/ciuz.19990330505Suche in Google Scholar

[29] Lipsky JJ, Shen ML, Naylor S. Overview – in vitro inhibition of aldehyde dehydrogenase by disulfiram and metabolites. Chem Biol Interact 2001; 130–132: 81–91.10.1016/S0009-2797(00)00224-6Suche in Google Scholar

[30] Löbler M, Sternberg K, Stachs O, et al. Polymers and drugs suitable for the development of a drug delivery drainage system in glaucoma surgery. J Biomed Mater Res B Appl Biomater 2011; 97: 388–395.10.1002/jbm.b.31826Suche in Google Scholar PubMed

[31] Luderer F, Begerow I, Schmidt W, et al Enhanced visualization of biodegradable polymeric vascular scaffolds by incorporation of gold, silver and magnetite nanoparticles. J Biomater Appl 2012 [Epub ahead of print].10.1177/0885328212443393Suche in Google Scholar PubMed

[32] Luderer F, Löbler M, Rohm HW, et al. Biodegradable sirolimus-loaded poly(lactide) nanoparticles as drug delivery system for the prevention of in-stent restenosis in coronary stent application. J Biomater Appl 2011; 25: 851–875.10.1177/0885328209360696Suche in Google Scholar PubMed

[33] Marks AR. Cellular functions of immunophilins. Physiol Rev 1996; 76: 631–649.10.1152/physrev.1996.76.3.631Suche in Google Scholar

[34] Martin DP, Williams SF. Medical applications of poly-4-hydroxybutyrate: a strong flexible absorbable biomaterial. Biochem Eng J 2003; 16: 97–105.10.1016/S1369-703X(03)00040-8Suche in Google Scholar

[35] Marx SO, Jayaraman T, Go LO, Marks AR. Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ Res 1995; 76: 412–417.10.1161/01.RES.76.3.412Suche in Google Scholar

[36] Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 1986; 46: 6387–6392.Suche in Google Scholar

[37] Meiser BM, Morris RE, Billingham ME. Effects of cyclosporin, FK506, and rapamycin on graft-vessel disease. Lancet 1991; 338: 1297–1298.10.1016/0140-6736(91)92594-RSuche in Google Scholar

[38] Minelli C, Lowe SB, Stevens MM. Engineering nanocomposite materials for cancer therapy. Small 2010; 6: 2336–2357.10.1002/smll.201000523Suche in Google Scholar

[39] Miyata T, Asami N, Uragami T. A reversibly antigen-responsive hydrogel. Nature 1999; 399: 766–769.10.1038/21619Suche in Google Scholar

[40] Miyata T, Asami N, Uragami T. Structural design of stimuli-responsive bioconjugated hydrogels that respond to a target antigen. J Polym Sci B Polymer Phys 2009; 47: 2144–2157.10.1002/polb.21812Suche in Google Scholar

[41] Moellering D, McAndrew J, Jo H, Darley-Usmar VM. Effects of pyrrolidine dithiocarbamate on endothelial cells: protection against oxidative stress. Free Radic Biol Med 1999; 26: 1138–1145.10.1016/S0891-5849(98)00300-1Suche in Google Scholar

[42] Mohacsi PJ, Tüller D, Hulliger B, Wijngaard PL. Different inhibitory effects of immunosuppressive drugs on human and rat aortic smooth muscle and endothelial cell proliferation stimulated by platelet-derived growth factor or endothelial cell growth factor. J Heart Lung Transplant 1997; 16: 484–492.Suche in Google Scholar

[43] Moon JI, Kim YS, Kim MS, et al. Effect of cyclosporine, mycophenolic acid, and rapamycin on the proliferation of rat aortic vascular smooth muscle cells: in vitro study. Transplant Proc 2000; 32: 2026–2027.10.1016/S0041-1345(00)01542-6Suche in Google Scholar

[44] Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002; 346: 1773–1780.10.1056/NEJMoa012843Suche in Google Scholar PubMed

[45] Nebeker JR, Virmani R, Bennett CL, et al. Hypersensitivity cases associated with drug-eluting coronary stents: a review of available cases from the Research on Adverse Drug Events and Reports (RADAR) project. J Am Coll Cardiol 2006; 47: 175–181.10.1016/j.jacc.2005.07.071Suche in Google Scholar PubMed

[46] Poon M, Marx SO, Gallo R, Badimon JJ, Taubman MB, Marks AR. Rapamycin inhibits vascular smooth muscle cell migration. J Clin Invest 1996; 98: 2277–2283.10.1172/JCI119038Suche in Google Scholar PubMed PubMed Central

[47] Regar E, Sianos G, Serruys PW. Stent development and local drug delivery. Br Med Bull 2001; 59: 227–248.10.1093/bmb/59.1.227Suche in Google Scholar PubMed

[48] Schultz D, Skamarauskas JT, Law N, Mitchinson MJ, Hunt JV. The inhibition of foam cell formation by sodium diethyldithiocarbamate. Free Radic Res 1995; 23: 259–271.10.3109/10715769509064039Suche in Google Scholar PubMed

[49] Serruys PW, De Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med 1994; 331: 489–495.10.1056/NEJM199408253310801Suche in Google Scholar PubMed

[50] Shian S-G, Kao Y-R, Wu FY-H, Wu C-W. Inhibition of invasion and angiogenesis by zinc-chelating agent disulfiram. Mol Pharmacol 2003; 64: 1076–1084.10.1124/mol.64.5.1076Suche in Google Scholar PubMed

[51] Sternberg K, Kramer S, Nischan C, et al. In vitro study of drug-eluting stent coatings based on poly(l-lactide) incorporating cyclosporine A – drug release, polymer degradation and mechanical integrity. J Mater Sci Mater Med 2007; 18: 1423–1432.10.1007/s10856-007-0148-8Suche in Google Scholar PubMed

[52] Sternberg K, Petersen S, Grabow N, et al. Implant-associated local drug delivery systems for different medical applications. Biomed Tech (Berl) 2012; 57(Suppl. 1): 393–396.10.1515/bmt-2012-4473Suche in Google Scholar

[53] Stoltenberg RL, Geraghty J, Steele DM, Kennedy E, Hullett DA, Sollinger HW. Inhibition of intimal hyperplasia in rat aortic allografts with cyclosporine. Transplantation 1995; 60: 993–998.10.1097/00007890-199511150-00020Suche in Google Scholar

[54] Taylor RD, Maners AW, Salari H, Baker M, Walker EM Jr. Disulfiram as a radiation modifier. Ann Clin Lab Sci 1986; 16: 443–449.Suche in Google Scholar

[55] Van de Water TR, Dinh CT, Vivero R, et al. Mechanisms of hearing loss from trauma and inflammation: otoprotective therapies from the laboratory to the clinic. Acta Otolaryngol 2010; 130: 308–311.10.3109/00016480903124655Suche in Google Scholar

[56] Wang AZ, Langer R, Farokhzad OC. Nanoparticle delivery of cancer drugs. Annu Rev Med 2012; 63: 185–198.10.1146/annurev-med-040210-162544Suche in Google Scholar PubMed

[57] Wang W, McLeod HL, Cassidy J. Disulfiram-mediated inhibition of NF-kappaB activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines. Int J Cancer 2003; 104: 504–511.10.1002/ijc.10972Suche in Google Scholar PubMed

[58] Wulf K, Teske M, Löbler M, Luderer F, Schmitz K-P, Sternberg K. Surface functionalization of poly(ε-caprolactone) improves its biocompatibility as scaffold material for bioartificial vessel prostheses. J Biomed Mater Res B Appl Biomater 2011; 98B: 89–100.10.1002/jbm.b.31836Suche in Google Scholar PubMed

[59] Yilmaz B, Cetin M, Palabiyik SS, Asci A. HPLC method for determination of disulfiram in pharmaceutical preparations. Alfa Univ Int J Chem 2010; 1: 79–86.Suche in Google Scholar

Received: 2012-12-14
Accepted: 2013-5-17
Published Online: 2013-06-12
Published in Print: 2013-10-01

©2013 by Walter de Gruyter Berlin Boston

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