Continuous glucose monitoring devices remain limited in their duration of use due to difficulties presented by the foreign body response (FBR), which impairs sensor functionality immediately following implantation via biofouling and leukocyte infiltration. The FBR persists through the life of the implant, culminating with fibrous encapsulation and isolation from normal tissue. These issues have led researchers to develop strategies to mitigate the FBR and improve tissue integration. Studies have often focused on abating the FBR using various outer coatings, thereby changing the chemical or physical characteristics of the sensor surface. While such strategies have led to some success, they have failed to fully integrate the sensor into surrounding tissue. To further address biocompatibility, researchers have designed coatings capable of actively releasing biological agents (e.g., vascular endothelial growth factor, dexamethasone, and nitric oxide) to direct the FBR to induce tissue integration. Active release approaches have proven promising and, when combined with biocompatible coating materials, may ultimately improve the in vivo lifetime of subcutaneous glucose biosensors. This article focuses on strategies currently under development for mitigating the FBR.
WilsonGSZhangY. Introduction to the glucose sensing problem. In: CunninghamDDStenkenJA, eds. In vivo glucose sensing. Hoboken: John Wiley & Sons; 2009.
2.
AndersonJM. Biological responses to materials. Annu Rev Mater Res.2001;31 (1): 81–110.
3.
AndersonJMRodriguezAChangDT. Foreign body reaction to biomaterials. Semin Immunol.2008;20 (2): 86–100.
4.
Thomé-DuretVGangnerauMNZhangYWilsonGSReachG. Modification of the sensitivity of glucose sensor implanted into subcutaneous tissue. Diabetes Metab.1996;22 (3): 174–8.
5.
GerritsenMJansenJAKrosAVriezemaDMSommerdijkNANolteRJLuttermanJAVan HövellSWVan der GaagA. Influence of inflammatory cells and serum on the performance of implantable glucose sensors. J Biomed Mater Res.2001;54 (1): 69–75.
6.
WilsonGSHuY. Enzyme-based biosensors for in vivo measurements. Chem Rev.2000;100 (7): 2693–704.
7.
ForsterJMorrisASShearerJDMastrofrancescoBInmanKCLawlerRGBowenWCaldwellMD. Glucose uptake and flux through phosphofructokinase in wounded rat skeletal muscle. Am J Physiol.1989;256 (6 Pt 1): E788–97.
8.
ZhaoQHMcNallyAKRubinKRRenierMWuYRose-CapraraVAndersonJMHiltnerAUrbanskiPStokesK. Human plasma alpha 2-macroglobulin promotes in vitro oxidative stress cracking of Pellethane 2363–80A: in vivo and in vitro correlations. J Biomed Mater Res.1993;27 (3): 379–88.
9.
AndersonJMDefifeKMcNallyACollierTJenneyC. Monocyte, macrophage and foreign body giant cell interactions with molecularly engineered surfaces. J Mater Sci Mater Med.1999;10 (10): 579–88.
10.
KluehUKaurMQiaoYKreutzerDL. Critical role of tissue mast cells in controlling long-term glucose sensor function in vivo. Biomaterials.2010;31 (16): 4540–51.
11.
SharkawyAAKlitzmanBTruskeyGAReichertWM. Engineering the tissue which encapsulates subcutaneous implants. I. Diffusion properties. J Biomed Mater Res.1997;37 (3): 401–12.
12.
JableckiMGoughDA. Simulations of the frequency response of implantable glucose sensors. Anal Chem.2000;72 (8): 1853–9.
13.
BrodbeckWGVoskericianGZiatsNPNakayamaYMatsudaTAndersonJM. In vivo leukocyte cytokine mRNA responses to biomaterials are dependent on surface chemistry. J Biomed Mater Res A.2003;64 (2): 320–9.
14.
DinnesDLMarçalHMahlerSMSanterreJPLabowRS. Material surfaces affect the protein expression patterns of human macrophages: A proteomics approach. J Biomed Mater Res A.2007;80 (4): 895–908.
15.
JuYMYuBKoobTJMoussyYMoussyF. A novel porous collagen scaffold around an implantable biosensor for improving biocompatibility. I. In vitro/in vivo stability of the scaffold and in vitro sensitivity of the glucose sensor with scaffold. J Biomed Mater Res A.2008;87 (1): 136–46.
16.
JuYMYuBWestLMoussyYMoussyF. A novel porous collagen scaffold around an implantable biosensor for improving biocompatibility. II. Long-term in vitro/in vivo sensitivity characteristics of sensors with NDGA- or GA-crosslinked collagen scaffolds. J Biomed Mater Res A.2010;92 (2): 650–8.
17.
WengLRomanovARooneyJChenW. Non-cytotoxic, in situ gelable hydrogels composed of N-carboxyethyl chitosan and oxidized dextran. Biomaterials.2008;29 (29): 3905–13.
18.
CaiZKimJ. Bacterial cellulose/poly(ethylene glycol) composite: Characterization and first evaluation of biocompatibility. Cellulose.2010;17 (1): 83–91.
19.
HeleniusGBäckdahlHBodinANannmarkUGatenholmPRisbergB. In vivo biocompatibility of bacterial cellulose. J Biomed Mater Res A.2006;76 (2): 431–8.
20.
GoDHJoungYKParkSYParkYDParkKD. Heparin-conjugated star-shaped PLA for improved biocompatibility. J Biomed Mater Res A.2008;86 (3): 842–8.
21.
DrayeJPDelaeyBVan de VoordeAVan Den BulckeADe ReuBSchachtE. In vitro and in vivo biocompatibility of dextran dialdehyde cross-linked gelatin hydrogel films. Biomaterials.1998;19 (18): 1677–87.
22.
CadéeJAvan LuynMJBrouwerLAPlantingaJAvan WachemPBde GrootCJden OtterWHenninkWE. In vivo biocompatibility of dextran-based hydrogels. J Biomed Mater Res.2000;50 (3): 397–404.
IshiharaKNomuraHMiharaTKuritaKIwasakiYNakabayashiN. Why do phospholipid polymers reduce protein adsorption?. J Biomed Mater Res.1998;39 (2): 323–30.
25.
KimKKimCByunY. Biostability and biocompatibility of a surface-grafted phospholipid monolayer on a solid substrate. Biomaterials.2004;25 (1): 33–41.
26.
SawadaSSakakiSIwasakiYNakabayashiNIshiharaK. Suppression of the inflammatory response from adherent cells on phospholipid polymers. J Biomed Mater Res A.2003;64 (3): 411–6.
27.
TurnerRFHarrisonDJRajotteRV. Preliminary in vivo biocompatibility studies on perfluorosulphonic acid polymer membranes for biosensor applications. Biomaterials.1991;12 (4): 361–8.
28.
MercadoRCMoussyF. In vitro and in vivo mineralization of Nafion membrane used for implantable glucose sensors. Biosens Bioelectron.1998;13 (2): 133–45.
29.
MoussyFHarrisonDJRajotteRV. A miniaturized Nafion-based glucose sensor: in vitro and in vivo evaluation in dogs. Int J Artif Organs.1994;17 (2): 88–94.
30.
JhonMSAndradeJD. Water and hydrogels. J Biomed Mater Res.1973;7 (6): 509–22.
31.
LeeKYMooneyDJ. Hydrogels for tissue engineering. Chem Rev.2001;101 (7): 1869–79.
32.
YuBWangCJuYMWestLHarmonJMoussyYMoussyF. Use of hydrogel coating to improve the performance of implanted glucose sensors. Biosens Bioelectron.2008;23 (8): 1278–84.
33.
QuinnCAConnorREHellerA. Biocompatible, glucose-permeable hydrogel for in situ coating of implantable biosensors. Biomaterials.1997;18 (24): 1665–70.
34.
WangCYuBKnudsenBHarmonJMoussyFMoussyY. Synthesis and performance of novel hydrogels coatings for implantable glucose sensors. Biomacromolecules.2008;9 (2): 561–7.
35.
NortonLWKoschwanezHEWisniewskiNAKlitzmanBReichertWM. Vascular endothelial growth factor and dexamethasone release from nonfouling sensor coatings affect the foreign body response. J Biomed Mater Res A.2007;81 (4): 858–69.
HarrisLDKimBSMooneyDJ. Open pore biodegradable matrices formed with gas foaming. J Biomed Mater Res.1998;42 (3): 396–402.
39.
HuaFJKimGELeeJDSonYKLeeDS. Macroporous poly(L-lactide) scaffold 1. Preparation of a macroporous scaffold by liquid-liquid phase separation of a PLLA–dioxane–water system. J Biomed Mater Res.2002;63 (2): 161–7.
YangSLeongKFDuZChuaCK. The design of scaffolds for use in tissue engineering. Part 1. Traditional factors. Tissue Eng.2001;7 (6): 679–89.
42.
KoschwanezHEYapFYKlitzmanBReichertWM. In vitro and in vivo characterization of porous poly-L-lactic acid coatings for subcutaneously implanted glucose sensors. J Biomed Mater Res A.2008;87 (3): 792–807.
43.
MarshallAJIrvinCABarkerTSageEHHauchKDRatnerBD. Biomaterials with tightly controlled pore size that promote vascular in-growth. ACS Polym Prepr.2004;45 (2): 100–1.
44.
SharkawyAAKlitzmanBTruskeyGAReichertWM. Engineering the tissue which encapsulates subcutaneous implants. II. Plasma-tissue exchange properties. J Biomed Mater Res.1998;40 (4): 586–97.
45.
IsenhathSNFukanoYUsuiMLUnderwoodRAIrvinCAMarshallAJHauchKDRatnerBDFleckmanPOlerudJE. A mouse model to evaluate the interface between skin and a percutaneous device. J Biomed Mater Res A.2007;83 (4): 915–22.
46.
DeligianniDDKatsalaNLadasSSotiropoulouDAmedeeJMissirlisYF. Effect of surface roughness of the titanium alloy Ti-6Al-4V on human bone marrow cell response and on protein adsorption. Biomaterials.2001;22 (11): 1241–51.
47.
RoachPFarrarDPerryCC. Surface tailoring for controlled protein adsorption: Effect of topography at the nanometer scale and chemistry. J Am Chem Soc.2006;128 (12): 3939–45.
48.
CaoHMcHughKChewSYAndersonJM. The topographical effect of electrospun nanofibrous scaffolds on the in vivo and in vitro foreign body reaction. J Biomed Mater Res A.2010;93 (3): 1151–9.
49.
BotaPCCollieAMPuolakkainenPVernonRBSageEHRatnerBDStaytonPS. Biomaterial topography alters healing in vivo and monocyte/macrophage activation in vitro. J Biomed Mater Res A.2010;95 (2): 649–57.
50.
PaulNESkazikCHarwardtMBartneckMDeneckeBKleeDSalberJZwadlo-KlarwasserG. Topographical control of human macrophages by a regularly microstructured polyvinylidene fluoride surface. Biomaterials.2008;29 (30): 4056–64.
51.
RefaiAKTextorMBrunetteDMWaterfieldJD. Effect of titanium surface topography on macrophage activation and secretion of proinflammatory cytokines and chemokines. J Biomed Mater Res A.2004;70 (2): 194–205.
52.
SoskolneWACohenSSennerbyLWennerbergAShapiraL. The effect of titanium surface roughness on the adhesion of monocytes and their secretion of TNF-alpha and PGE2. Clin Oral Implants Res.2002;13 (1): 86–93.
SungJBaronePWKongHStranoMS. Sequential delivery of dexamethasone and VEGF to control local tissue response for carbon nanotube fluorescence based micro-capillary implantable sensors. Biomaterials.2009;30 (4): 622–31.
55.
NortonLWTegnellEToporekSSReichertWM. In vitro characterization of vascular endothelial growth factor and dexamethasone releasing hydrogels for implantable probe coatings. Biomaterials.2005;26 (16): 3285–97.
56.
PatilSDPapadmitrakopoulosFBurgessDJ. Concurrent delivery of dexamethasone and VEGF for localized inflammation control and angiogenesis. J Control Release.2007;117 (1): 68–79.
57.
KluehUDorskyDIKreutzerDL. Enhancement of implantable glucose sensor function in vivo using gene transfer-induced neovascularization. Biomaterials.2005;26 (10): 1155–63.
58.
WardWKWoodMDCaseyHMQuinnMJFederiukIF. The effect of local subcutaneous delivery of vascular endothelial growth factor on the function of a chronically implanted amperometric glucose sensor. Diabetes Technol Ther.2004;6 (2): 137–45.
59.
WardWKQuinnMJWoodMDTiekotterKLPidikitiSGallagherJA. Vascularizing the tissue surrounding a model biosensor: How localized is the effect of a subcutaneous infusion of vascular endothelial growth factor (VEGF)?. Biosens Bioelectron.2003;19 (3): 155–63.
60.
FerraraNGerberH-PLeCouterJ. The biology of VEGF and its receptors. Nat Med.2003;9 (6): 669–76.
61.
KluehUDorskyDIKreutzerDL. Use of vascular endothelial cell growth factor gene transfer to enhance implantable sensor function in vivo. J Biomed Mater Res A.2003;67 (4): 1072–86.
62.
El AzabSRRosseelPMde LangeJJGroeneveldABvan StrikRvan WijkEMSchefferGJ. Dexamethasone decreases the pro- to anti-inflammatory cytokine ratio during cardiac surgery. Br J Anaesth.2002;88 (4): 496–501.
63.
StreckerEPGabelmannABoosILucasCXuZHaberstrohJFreudenbergNStrickerHLangerMBetzE. Effect on intimal hyperplasia of dexamethasone released from coated metal stents compared with non-coated stents in canine femoral arteries. Cardiovasc Intervent Radiol.1998;21 (6): 487–96.
64.
BeerHDFässlerRWernerS. Glucocorticoid-regulated gene expression during cutaneous wound repair. Vitam Horm.2000;59: 217–39.
65.
HickeyTKreutzerDBurgessDJMoussyF. In vivo evaluation of a dexamethasone/PLGA microsphere system designed to suppress the inflammatory tissue response to implantable medical devices. J Biomed Mater Res.2002;61 (2): 180–7.
EdelmanJLLutzDCastroMR. Corticosteroids inhibit VEGF-induced vascular leakage in a rabbit model of blood-retinal and blood-aqueous barrier breakdown. Exp Eye Res.2005;80 (2): 249–58.
68.
MacheinMRKullmerJRönickeVMacheinUKriegMDamertABreierGRisauWPlateKH. Differential downregulation of vascular endothelial growth factor by dexamethasone in normoxic and hypoxic rat glioma cells. Neuropathol Appl Neurobiol.1999;25 (2): 104–12.
69.
WuWSWangFSYangKDHuangCCKuoYR. Dexamethasone induction of keloid regression through effective suppression of VEGF expression and keloid fibroblast proliferation. J Invest Dermatol.2006;126 (6): 1264–71.
70.
WilliamsDL. A chemist's view of the nitric oxide story. Org Biomol Chem.2003;1 (3): 441–9.
71.
GiffordRBatchelorMMLeeYGokulranganGMeyerhoffMEWilsonGS. Mediation of in vivo glucose sensor inflammatory response via nitric oxide release. J Biomed Mater Res A.2005;75 (4): 755–66.
72.
ShinJHSchoenfischMH. Improving the biocompatibility of in vivo sensors via nitric oxide release. Analyst.2006;131 (5): 609–15.
73.
WangPGXianMTangXWuXWenZCaiTJanczukAJ. Nitric oxide donors: Chemical activities and biological applications. Chem Rev.2002;102 (4): 1091–134.
74.
Al-Sa'doniHHFerroA. S-nitrosothiols as nitric oxide-donors: Chemistry, biology and possible future therapeutic applications. Curr Med Chem.2004;11 (20): 2679–90.
75.
HetrickEMPrichardHLKlitzmanBSchoenfischMH. Reduced foreign body response at nitric oxide-releasing subcutaneous implants. Biomaterials.2007;28 (31): 4571–80.
76.
NabloBJSchoenfischMH. In vitro cytotoxicity of nitric oxide-releasing sol-gel derived materials. Biomaterials.2005;26 (21): 4405–15.
StaskoNASchoenfischMH. Dendrimers as a scaffold for nitric oxide release. J Am Chem Soc.2006;128 (25): 8265–71.
83.
JoYSvan der VliesAJGantzJThacherTNAntonijevicSCavadiniSDemurtasDStergiopulosNHubbellJA. Micelles for delivery of nitric oxide. J Am Chem Soc.2009;131 (40): 14413–8.
MoweryKASchoenfischMHSaavedraJEKeeferLKMeyerhoffME. Preparation and characterization of hydrophobic polymeric films that are thromboresistant via nitric oxide release. Biomaterials.2000;21 (1): 9–21.
88.
ParzuchowskiPGFrostMCMeyerhoffME. Synthesis and characterization of polymethacrylate-based nitric oxide donors. J Am Chem Soc.2002;124 (41): 12182–91.
89.
ZhouZMeyerhoffME. Polymethacrylate-based nitric oxide donors with pendant N-diazeniumdiolated alkyldiamine moieties: Synthesis, characterization, and preparation of nitric oxide releasing polymeric coatings. Biomacromolecules.2005;6 (2): 780–9.
90.
NicholsSPLeNNKlitzmanBSchoenfischMH. Increased in vivo glucose recovery via nitric oxide release. Anal Chem.2011;83 (4): 1180–4.
