Reduced foreign body response at nitric oxide-releasing subcutaneous implants.

The tissue response to nitric oxide (NO)-releasing subcutaneous implants is presented. Model implants were created by coating silicone elastomer with diazeniumdiolate-modified xerogel polymers capable of releasing NO. The host tissue response to such implants was evaluated at 1, 3, and 6 weeks and compared to that of uncoated silicone elastomer blanks and xerogel-coated controls incapable of releasing NO. Delivery of NO (approximately 1.35 micromol/cm2 of implant surface area) reduced foreign body collagen capsule ("scar tissue") thickness by >50% compared to uncoated silicone elastomer after 3 weeks. The chronic inflammatory response at the tissue/implant interface was also reduced by >30% at NO-releasing implants after 3 and 6 weeks. Additionally, CD-31 immunohistochemical staining revealed approximately 77% more blood vessels in proximity to NO-releasing implants after 1 week compared to controls. These findings suggest that conferring NO release to subcutaneous implants may promote effective device integration into healthy vascularized tissue, diminish foreign body capsule formation, and improve the performance of indwelling medical devices that require constant mass transport of analytes (e.g., implantable sensors).

[1]  David J Mooney,et al.  Coating of VEGF-releasing scaffolds with bioactive glass for angiogenesis and bone regeneration. , 2006, Biomaterials.

[2]  M. Meyerhoff,et al.  Preparation and characterization of hydrophobic polymeric films that are thromboresistant via nitric oxide release. , 2000, Biomaterials.

[3]  Mark E. Meyerhoff,et al.  Preparation and characterization of implantable sensors with nitric oxide release coatings , 2003 .

[4]  Chandan K Sen,et al.  Revisiting the essential role of oxygen in wound healing. , 2003, American journal of surgery.

[5]  Mark E Meyerhoff,et al.  Polymers incorporating nitric oxide releasing/generating substances for improved biocompatibility of blood-contacting medical devices. , 2005, Biomaterials.

[6]  M. Schoenfisch,et al.  Inhibition of implant-associated infections via nitric oxide release. , 2005, Biomaterials.

[7]  Megan C Frost,et al.  Implantable chemical sensors for real-time clinical monitoring: progress and challenges. , 2002, Current opinion in chemical biology.

[8]  Y. Nakayama,et al.  Spatial regulation and surface chemistry control of monocyte/macrophage adhesion and foreign body giant cell formation by photochemically micropatterned surfaces. , 1999, Journal of biomedical materials research.

[9]  D. Mooney,et al.  Polymers for pro- and anti-angiogenic therapy. , 2007, Biomaterials.

[10]  D. Bezuidenhout,et al.  Effect of Well Defined Dodecahedral Porosity on Inflammation and Angiogenesis , 2002, ASAIO journal.

[11]  Ivan Martin,et al.  Angiogenesis in tissue engineering: breathing life into constructed tissue substitutes. , 2006, Tissue engineering.

[12]  Lars M Bjursten,et al.  Anti-inflammatory properties of micropatterned titanium coatings. , 2006, Journal of biomedical materials research. Part A.

[13]  M. Schoenfisch,et al.  Antibacterial nitric oxide-releasing xerogels: cell viability and parallel plate flow cell adhesion studies. , 2007, Biomaterials.

[14]  B. Ratner,et al.  Design of infection-resistant antibiotic-releasing polymers: I. Fabrication and formulation. , 1999, Journal of controlled release : official journal of the Controlled Release Society.

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

[16]  D J Mooney,et al.  Spatiotemporal control of vascular endothelial growth factor delivery from injectable hydrogels enhances angiogenesis , 2007, Journal of thrombosis and haemostasis : JTH.

[17]  A. Chu,et al.  Up-regulation by human recombinant transforming growth factor beta-1 of collagen production in cultured dermal fibroblasts is mediated by the inhibition of nitric oxide signaling. , 1999, Journal of the American College of Surgeons.

[18]  B. Ratner.  Reducing capsular thickness and enhancing angiogenesis around implant drug release systems. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[19]  G. Prestwich,et al.  Stimulation of in vivo angiogenesis using dual growth factor-loaded crosslinked glycosaminoglycan hydrogels. , 2006, Biomaterials.

[20]  R. Shankar,et al.  Nitric oxide inhibits wound collagen synthesis , 1999, Molecular and Cellular Biochemistry.

[21]  Jian-dongLUO,et al.  Nitric oxide： a newly discovered function on wound healing , 2005 .

[22]  J. Cooke.  NO and angiogenesis. , 2003, Atherosclerosis. Supplements.

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

[24]  K. Olbrich,et al.  Halofuginone inhibits collagen deposition in fibrous capsules around implants. , 2005, Annals of plastic surgery.

[25]  Christian Bogdan,et al.  Nitric oxide and the immune response , 2001, Nature Immunology.

[26]  G. S. Wilson,et al.  Enzyme-based biosensors for in vivo measurements. , 2000, Chemical reviews.

[27]  G. S. Wilson,et al.  Biosensors for real-time in vivo measurements. , 2005, Biosensors & bioelectronics.

[28]  J. Botting,et al.  Non-steroidal anti-inflammatory drugs , 2005 .

[29]  Giridharan Gokulrangan,et al.  Mediation of in vivo glucose sensor inflammatory response via nitric oxide release. , 2005, Journal of biomedical materials research. Part A.

[30]  Jie Li,et al.  Angiogenesis in wound repair: Angiogenic growth factors and the extracellular matrix , 2003, Microscopy research and technique.

[31]  M. Meyerhoff,et al.  Improving the thromboresistivity of chemical sensors via nitric oxide release: fabrication and in vivo evaluation of NO-releasing oxygen-sensing catheters. , 2000, Analytical chemistry.

[32]  Jae Ho Shin,et al.  Improving the biocompatibility of in vivo sensors via nitric oxide release. , 2006, The Analyst.

[33]  Mary E. Robbins,et al.  Preparation of Nitric Oxide (NO)-Releasing Sol−Gels for Biomaterial Applications , 2003 .

[34]  George M. Whitesides,et al.  Surveying for Surfaces that Resist the Adsorption of Proteins , 2000 .

[35]  G. Raffaini,et al.  Sequential adsorption of proteins and the surface modification of biomaterials: A molecular dynamics study , 2007, Journal of materials science. Materials in medicine.

[36]  A. Józkowicz,et al.  Regulation of vascular endothelial growth factor synthesis by nitric oxide: facts and controversies. , 2003, Antioxidants & redox signaling.

[37]  F. DeRubertis,et al.  Nitric Oxide Inhibition of Transforming Growth Factor-β and Collagen Synthesis in Mesangial Cells , 1997, Diabetes.

[38]  J. Triffitt,et al.  A review on macrophage responses to biomaterials , 2006, Biomedical Materials.

[39]  M. Pett.  Nonparametric Statistics for Health Care Research: Statistics for Small Samples and Unusual Distributions , 1997 .

[40]  B. Ratner,et al.  The role of osteopontin in foreign body giant cell formation. , 2005, Biomaterials.

[41]  M. Parnham,et al.  Principles of immunopharmacology , 2005 .

[42]  Y. Vodovotz,et al.  Nitric oxide and wound repair: role of cytokines? , 2002, Nitric oxide : biology and chemistry.

[43]  D. Grainger,et al.  Polyurethane coatings release bioactive antibodies to reduce bacterial adhesion. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[44]  S. Moncada,et al.  Biphasic Regulation of NF-κB Activity Underlies the Pro- and Anti-Inflammatory Actions of Nitric Oxide1 , 2001, The Journal of Immunology.

[45]  T. Ogata,et al.  Pharmacokinetic interactions of flunixin meglumine and enrofloxacin in dogs. , 2005, American journal of veterinary research.