Controlled release of heparin from poly(ε-caprolactone) electrospun fibers

Sustained delivery of heparin to the localized adventitial surface of grafted blood vessels has been shown to prevent the vascular smooth muscle cell (VSMC) proliferation that can lead to graft occlusion and failure. In this study heparin was incorporated into electrospun poly(e-caprolactone) (PCL) fiber mats for assessment as a controlled delivery device. Fibers with smooth surfaces and no bead defects could be spun from polymer solutions with 8% w/v PCL in 7:3 dichloromethane:methanol. A significant decrease in fiber diameter was observed with increasing heparin concentration. Assessment of drug loading, and imaging of fluorescently labeled heparin showed homogenous distribution of heparin throughout the fiber mats. A total of approximately half of the encapsulated heparin was released by diffusional control from the heparin/PCL fibers after 14 days. The fibers did not induce an inflammatory response in macrophage cells in vitro and the released heparin was effective in preventing the proliferation of VSMCs in culture. These results suggest that electrospun PCL fibers are a promising candidate for delivery of heparin to the site of vascular injury.

[1]  Myung-Seob Khil,et al.  Characterization of nano-structured poly(ε-caprolactone) nonwoven mats via electrospinning , 2003 .

[2]  K. Mishra-Gorur,et al.  Heparin rapidly and selectively regulates protein tyrosine phosphorylation in vascular smooth muscle cells , 1999, Journal of cellular physiology.

[3]  B. Caleb,et al.  Heparin inhibits c-fos and c-myc mRNA expression in vascular smooth muscle cells. , 1990, Cell regulation.

[4]  E. Edelman,et al.  Inhibition of experimental neointimal hyperplasia and thrombosis depends on the type of vascular injury and the site of drug administration. , 1993, Circulation.

[5]  P. Maincent,et al.  Preparation and Characterization of Heparin-Loaded Polymeric Microparticles , 2002, Drug development and industrial pharmacy.

[6]  Clowes Aw,et al.  Kinetics of cellular proliferation after arterial injury. II. Inhibition of smooth muscle growth by heparin. , 1985, Laboratory investigation; a journal of technical methods and pathology.

[7]  Myung-Seob Khil,et al.  Electrospun nanofibrous polyurethane membrane as wound dressing. , 2003, Journal of biomedical materials research. Part B, Applied biomaterials.

[8]  S. Shivkumar,et al.  N,N-Dimethylformamide Additions to the Solution for the Electrospinning of Poly(ε-caprolactone) Nanofibers , 2004 .

[9]  Seeram Ramakrishna,et al.  Electrospinning of gelatin fibers and gelatin/PCL composite fibrous scaffolds. , 2005, Journal of biomedical materials research. Part B, Applied biomaterials.

[10]  M. Sefton.  Biomaterials and Clinical Applications , 1988 .

[11]  E. Edelman,et al.  Perivascular graft heparin delivery using biodegradable polymer wraps. , 2000, Biomaterials.

[12]  A. Nicolaides,et al.  Graft stenosis: Justification for 1 ‐year surveillance , 1990, The British journal of surgery.

[13]  R. Rosenberg,et al.  Inhibition of Rat Arterial Smooth Muscle Cell Proliferation by Heparin: II. In Vitro Studies , 1980, Circulation research.

[14]  E. Edelman,et al.  Effect of controlled adventitial heparin delivery on smooth muscle cell proliferation following endothelial injury. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[15]  W. Kett,et al.  Protein-heparin interactions measured by BIAcore 2000 are affected by the method of heparin immobilization. , 2002, Analytical biochemistry.

[16]  M. Karnovsky,et al.  Inhibition of vascular smooth muscle cell growth by endothelial cell-derived heparin. Possible role of a platelet endoglycosidase. , 1982, The Journal of biological chemistry.

[17]  V. Babak,et al.  Low Molecular Weight Heparin-Loaded Polymeric Nanoparticles: Formulation, Characterization, and Release Characteristics , 2002, Drug development and industrial pharmacy.

[18]  A. Clowes,et al.  Suppression by heparin of smooth muscle cell proliferation in injured arteries , 1977, Nature.

[19]  Xuesi Chen,et al.  Ultrafine fibers electrospun from biodegradable polymers , 2003 .

[20]  A. Clowes,et al.  Heparin inhibits the induction of three matrix metalloproteinases (stromelysin, 92-kD gelatinase, and collagenase) in primate arterial smooth muscle cells. , 1994, The Journal of clinical investigation.

[21]  W. Cohn.  Surgical coronary revascularization remains relevant in the era of stents , 2004, Current opinion in cardiology.

[22]  Lixin Yang,et al.  Biodegradable electrospun fibers for drug delivery. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[23]  Kwangsok Kim,et al.  Structure and process relationship of electrospun bioabsorbable nanofiber membranes , 2002 .

[24]  Cato T Laurencin,et al.  Bioresorbable nanofiber-based systems for wound healing and drug delivery: optimization of fabrication parameters. , 2004, Journal of biomedical materials research. Part B, Applied biomaterials.

[25]  R. Langer,et al.  Biodegradable polymers as drug delivery systems , 1990 .

[26]  M. Kotaki,et al.  A review on polymer nanofibers by electrospinning and their applications in nanocomposites , 2003 .

[27]  C. Booth,et al.  Preparation and characterization of poly(ε-caprolactone) polymer blends for the delivery of proteins , 1995 .

[28]  J. Vacanti,et al.  A biodegradable nanofiber scaffold by electrospinning and its potential for bone tissue engineering. , 2003, Biomaterials.

[29]  Joseph P Vacanti,et al.  In vivo bone tissue engineering using mesenchymal stem cells on a novel electrospun nanofibrous scaffold. , 2004, Tissue engineering.

[30]  Joel Rosenblatt,et al.  Incorporation of drugs in an amorphous state into electrospun nanofibers composed of a water-insoluble, nonbiodegradable polymer. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[31]  E. Vogler,et al.  Systematic variation in osteoblast adhesion and phenotype with substratum surface characteristics. , 2004, Journal of biomedical materials research. Part A.

[32]  B. Hsiao,et al.  Development of a nanostructured DNA delivery scaffold via electrospinning of PLGA and PLA-PEG block copolymers. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[33]  Y. Ikada,et al.  In Vitro Evaluation of Sustained Drug Release from Biodegradable Elastomer , 1991, Pharmaceutical Research.

[34]  T. Higuchi.  MECHANISM OF SUSTAINED-ACTION MEDICATION. THEORETICAL ANALYSIS OF RATE OF RELEASE OF SOLID DRUGS DISPERSED IN SOLID MATRICES. , 1963, Journal of pharmaceutical sciences.

[35]  M. Kotaki,et al.  Guided bone regeneration membrane made of polycaprolactone/calcium carbonate composite nano-fibers. , 2005, Biomaterials.

[36]  R. Jaeger,et al.  Electrospinning of ultra-thin polymer fibers , 1998 .

[37]  Kwangsok Kim,et al.  Incorporation and controlled release of a hydrophilic antibiotic using poly(lactide-co-glycolide)-based electrospun nanofibrous scaffolds. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[38]  V. Crescenzi,et al.  Thermodynamics of fusion of poly-β-propiolactone and poly-ϵ-caprolactone. comparative analysis of the melting of aliphatic polylactone and polyester chains , 1972 .

[39]  B. Vincent,et al.  Controlled release of 4-nitroanisole from poly(lactic acid) nanoparticles. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[40]  M. Karnovsky,et al.  Inhibition of vein graft intimal proliferative lesions in the rat by heparin. , 1991, The American journal of pathology.

[41]  John Layman,et al.  Release of tetracycline hydrochloride from electrospun poly(ethylene-co-vinylacetate), poly(lactic acid), and a blend. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[42]  G. Montalescot,et al.  Myocardial Viability in Patients With Q Wave Myocardial Infarction and No Residual Ischemia , 1992, Circulation.

[43]  Joel Rosenblatt,et al.  Preparation and physicochemical characterization of biodegradable nerve guides containing the nerve growth agent sabeluzole. , 2005, Biomaterials.

[44]  A. Jayakrishnan,et al.  Protein release from poly(epsilon-caprolactone) microspheres prepared by melt encapsulation and solvent evaporation techniques: a comparative study. , 1997, Journal of biomaterials science. Polymer edition.

[45]  D Schwartz,et al.  A Cascade Model for Restenosis: A Special Case of Atherosclerosis Progression , 1992, Circulation.

[46]  J. Han,et al.  Improved blood compatibility by sustained release of heparin–deoxycholic acid conjugates in a PCL–PEG multiblock copolymer matrix , 2002, Journal of biomaterials science. Polymer edition.