PLGA/PVA hydrogel composites for long-term inflammation control following s.c. implantation.

Dexamethasone loaded PLGA microsphere/PVA hydrogel composites were investigated as an outer drug-eluting coating for implantable devices to provide protection against the foreign body response. Two populations of microspheres were prepared: 25 kDa PLGA microspheres which had a typical triphasic release profile extending over 30-33 days; and 75 kDa PLGA microspheres which showed minimal release for the first 25 days and then increased to release over 80-85 days. Incorporation of the microspheres in the composites only slightly altered the release profile. Composites containing 25 kDa microspheres released dexamethasone over 30-35 days while composites containing combinations of 25 and 75 kDa microspheres in equal amounts released over 90-95 days. Pharmacodynamic studies showed that composites containing only 25 kDa microspheres provided protection against the inflammatory response for 1 month, however, a delayed tissue reaction developed after exhaustion of dexamethasone. This demonstrated that sustained release of the anti-inflammatory agent is required over the entire implant lifetime to control inflammation and prevent fibrosis. Composites fabricated using combinations of 25 kDa and 75 kDa microspheres controlled the tissue reaction for 90 days. This strategy of combining different microsphere populations in the same composite coating can be used to tune the release profiles for the desired extent and duration of release. Such composites offer an innovative solution to control the foreign body response at the tissue-device interface.

[1]  S. Genuth,et al.  The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. , 1993, The New England journal of medicine.

[2]  F. Papadimitrakopoulos,et al.  Dexamethasone-loaded poly(lactic-co-glycolic) acid microspheres/poly(vinyl alcohol) hydrogel composite coatings for inflammation control. , 2004, Diabetes technology & therapeutics.

[3]  R. Holman,et al.  Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. , 1998 .

[4]  Buddy D Ratner,et al.  Biomaterials: where we have been and where we are going. , 2004, Annual review of biomedical engineering.

[5]  T. Stedeford,et al.  The development of minimally invasive continuous Metabolic Monitoring Technologies in the U.S. Army TMM Research Program. , 2005, Diabetes technology & therapeutics.

[6]  M. Langer,et al.  Effect on intimal hyperplasia of dexamethasone released from coated metal stents compared with non-coated stents in canine femoral arteries , 1998, CardioVascular and Interventional Radiology.

[7]  M. Savage,et al.  A controlled trial of corticosteroids to prevent restenosis after coronary angioplasty. M-HEART Group. , 1990, Circulation.

[8]  M Gerritsen,et al.  Problems associated with subcutaneously implanted glucose sensors. , 2000, Diabetes care.

[9]  D. Simon,et al.  Inflammation as a mechanism and therapeutic target for in-stent restenosis , 2005, Current atherosclerosis reports.

[10]  Joseph Wang,et al.  Glucose Biosensors : 40 Years of Advances and Challenges , 2001 .

[11]  Rebecca S. Shawgo,et al.  Biocompatibility and biofouling of MEMS drug delivery devices. , 2003, Biomaterials.

[12]  W M Reichert,et al.  Engineering the tissue which encapsulates subcutaneous implants. I. Diffusion properties. , 1997, Journal of biomedical materials research.

[13]  Pauline E. Leary,et al.  Elevated temperature accelerated release testing of PLGA microspheres. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[14]  J. Jansen,et al.  Performance of subcutaneously implanted glucose sensors for continuous monitoring. , 1999, The Netherlands journal of medicine.

[15]  Fotios Papadimitrakopoulos,et al.  Controlling Acute Inflammation with Fast Releasing Dexamethasone-PLGA Microsphere/PVA Hydrogel Composites for Implantable Devices , 2007, Journal of diabetes science and technology.

[16]  F Moussy,et al.  In vivo evaluation of a dexamethasone/PLGA microsphere system designed to suppress the inflammatory tissue response to implantable medical devices. , 2002, Journal of biomedical materials research.

[17]  Peter T Kissinger,et al.  Biosensors-a perspective. , 2005, Biosensors & bioelectronics.

[18]  G. S. Wilson,et al.  Progress toward the development of an implantable sensor for glucose. , 1992, Clinical chemistry.

[19]  D. Burgess,et al.  Application of USP Apparatus 4 and In Situ Fiber Optic Analysis to Microsphere Release Testing , 2005 .

[20]  Huangxian Ju,et al.  Reagentless glucose biosensor based on direct electron transfer of glucose oxidase immobilized on colloidal gold modified carbon paste electrode. , 2003, Biosensors & bioelectronics.

[21]  G. Y. Daniloff.  Continuous glucose monitoring: long-term implantable sensor approach. , 1999, Diabetes technology & therapeutics.

[22]  W Kerner,et al.  Implantable glucose sensors: present status and future developments. , 2001, Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association.

[23]  T. Webster,et al.  Biological Responses to and Toxicity of Nanoscale Implant Materials , 2012 .

[24]  James M. Anderson,et al.  Local release of dexamethasone from polymer millirods effectively prevents fibrosis after radiofrequency ablation. , 2006, Journal of biomedical materials research. Part A.

[25]  Joseph Wang,et al.  Glucose Biosensors: 40 Years of Advances and Challenges , 2001 .

[26]  Diane J Burgess,et al.  Concurrent delivery of dexamethasone and VEGF for localized inflammation control and angiogenesis. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[27]  D J Claremont,et al.  In vitro testing of a simply constructed, highly stable glucose sensor suitable for implantation in diabetic patients. , 1991, Biosensors & bioelectronics.

[28]  E. Topol,et al.  Marked inflammatory sequelae to implantation of biodegradable and nonbiodegradable polymers in porcine coronary arteries. , 1996, Circulation.

[29]  L. Heinemann,et al.  Sensors for glucose monitoring: technical and clinical aspects , 2001, Diabetes/metabolism research and reviews.

[30]  K. Stevens,et al.  In vivo biocompatibility of gelatin-based hydrogels and interpenetrating networks , 2002, Journal of biomaterials science. Polymer edition.

[31]  Peter G Jacobs,et al.  Feasibility of continuous long-term glucose monitoring from a subcutaneous glucose sensor in humans. , 2004, Diabetes technology & therapeutics.

[32]  G. Stone,et al.  A randomized trial of corticosteroids for the prevention of restenosis in 102 patients undergoing repeat coronary angioplasty. , 1989, Catheterization and cardiovascular diagnosis.

[33]  G. S. Wilson,et al.  Towards continuous glucose monitoring: in vivo evaluation of a miniaturized glucose sensor implanted for several days in rat subcutaneous tissue , 1992, Diabetologia.

[34]  Fotios Papadimitrakopoulos,et al.  Controlled release of dexamethasone from PLGA microspheres embedded within polyacid-containing PVA hydrogels , 2005, The AAPS Journal.

[35]  F Moussy,et al.  Dexamethasone/PLGA microspheres for continuous delivery of an anti-inflammatory drug for implantable medical devices. , 2002, Biomaterials.

[36]  N. Wisniewski,et al.  Decreased analyte transport through implanted membranes: differentiation of biofouling from tissue effects. , 2001, Journal of biomedical materials research.

[37]  Vinay Kumar,et al.  Acute and Chronic Inflammation , 2010 .