A major obstacle to the development of implantable biosensors is the foreign body response (FBR) that results from tissue trauma during implantation and the continuous presence of the implant in the body. The in vivo stability and functionality of biosensors are compromised by damage to sensor components and decreased analyte transport to the sensor. This paper summarizes research undertaken by our group since 2001 to control the FBR toward implanted sensors. Localized and sustained delivery of the anti-inflammatory drug, dexamethasone, and the angiogenic growth factor, vascular endothelial growth factor (VEGF), was utilized to inhibit inflammation as well as fibrosis and provide a stable tissue-device interface without producing systemic adverse effects. The drug-loaded polylactic-co-glycolic acid (PLGA) microspheres were embedded in a polyvinyl alcohol (PVA) hydrogel composite to fabricate a drug-eluting, permeable external coating for implantable devices. The composites were fabricated using the freeze-thaw cycle method and had mechanical properties similar to soft body tissue. Dexamethasone-loaded microsphere/hydrogel composites were able to provide anti-inflammatory protection, preventing the FBR. Moreover, concurrent release of dexamethasone with VEGF induced neoangiogenesis in addition to providing anti-inflammatory protection. Sustained release of dexamethasone is required for the entire sensor lifetime, as a delayed inflammatory response developed after depletion of the drug from the composites. These studies have shown the potential of PLGA microsphere/PVA hydrogel-based composites as drug-eluting external coatings for implantable biosensors.
LoisanceD.Cardiac assist devices: present status and future opportunities. Expert Rev Med Devices. 2004;1 (1): 43–8.
2.
LearmonthIDYoungCRorabeckC.The operation of the century: total hip replacement. Lancet. 2007;370 (9597): 1508–19.
3.
OhSHKangSGKimESChoSHLeeJH.Fabrication and characterization of hydrophilic poly(lactic-co-glycolic acid)/poly(vinyl alcohol) blend cell scaffolds by melt-molding particulate-leaching method. Biomaterials. 2003;24 (22): 4011–21.
4.
ShinHRuhéP QuintenMikosAGJansenJA.In vivo bone and soft tissue response to injectable, biodegradable oligo(poly(ethylene glycol) fumarate) hydrogels. Biomaterials. 2003;24 (19): 3201–11.
5.
WilsonGSZhangYReachGMoatti-SiratDPoitoutVThévenotDRLemonnierFKleinJC.Progress toward the development of an implantable sensor for glucose. Clin Chem. 1992;38 (9): 1613–7.
Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329 (14): 977–86.
8.
United Kingdom Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352 (9131): 837–53.
9.
ClarkLCJrLyonsC. Electrode systems for continuous monitoring in cardiovascular surgery. Ann N Y Acad Sci. 1962;102: 29–45.
10.
GilliganBCShultsMRhodesRKJacobsPGBraukerJHPintarTJUpdikeSJ.Feasibility of continuous long-term glucose monitoring from a subcutaneous glucose sensor in humans. Diabetes Technol Ther. 2004;6 (3): 378–86.
Moatti-SiratDCapronFPoitoutVReachGBindraDSZhangYWilsonGSThévenotDR.Towards continuous glucose monitoring: in vivo evaluation of a miniaturized glucose sensor implanted for several days in rat subcutaneous tissue. Diabetologia. 1992;35 (3): 224–30.
13.
AndersonJM.Biological responses to materials. Annu Rev Mater Res. 2001;31: 81–110.
14.
van der GiessenWJLincoffAMSchwartzRSvan BeusekomHMSerruysPWHolmesDRJrEllisSGTopolEJ.Marked inflammatory sequelae to implantation of biodegradable and nonbiodegradable polymers in porcine coronary arteries. Circulation. 1996;94 (7): 1690–7.
15.
MitchellRNCotranRS.Acute and chronic inflammation in Robbins basic pathology. 7 ed.Philadelphia: Saunders; 2002.
16.
GerritsenMJansenJALuttermanJA.Performance of subcutaneously implanted glucose sensors for continuous monitoring. Neth J Med. 1999;54 (4): 167–79.
17.
WisniewskiNKlitzmanBMillerBReichertWM.Decreased analyte transport through implanted membranes: differentiation of biofouling from tissue effects. J Biomed Mater Res. 2001;57 (4): 513–21.
18.
GiffordRKehoeJJBarnesSLKornilayevBAAltermanMAWilsonGS.Protein interactions with subcutaneously implanted biosensors. Biomaterials. 2006;27 (12): 2587–98.
19.
SharkawyAAKlitzmanBTruskeyGAReichertWM.Engineering the tissue which encapsulates subcutaneous implants. I. Diffusion properties. J Biomed Mater Res. 1997;37 (3): 401–12.
20.
KlonoffDC.Technological advances in the treatment of diabetes mellitus: better bioengineering begets benefits in glucose measurement, the artificial pancreas, and insulin delivery. Pediatr Endocrinol Rev. 2003;1 (2): 94–100.
21.
BaileyTSZisserHCGargSK.Reduction in hemoglobin A1C with real-time continuous glucose monitoring: results from a 12-week observational study. Diabetes Technol Ther. 2007;9 (3): 203–10.
BhardwajUSuraRPapadimitrakopoulosFBurgessDJ.Controlling acute inflammation with fast releasing dexamethasone-PLGA microsphere/PVA hydrogel composites for implantable devices. J Diabetes Sci Technol. 2007;1 (1): 8–17.
24.
GaleskaIKimTKPatilSDBhardwajUChatttopadhyayDPapadimitrakopoulosFBurgessDJ.Controlled release of dexamethasone from PLGA microspheres embedded within polyacid-containing PVA hydrogels. AAPS J. 2005;7 (1): E231–40.
25.
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.
PatilSDPapadmitrakopoulosFBurgessDJ.Concurrent delivery of dexamethasone and VEGF for localized inflammation control and angiogenesis. J Control Release. 2007;117 (1): 68–79.
28.
SchimmerBParkerK.Adrenocorticotropic hormone; adrenocortical steroids and their synthetic anlogues; inhibitors of the synthesis and actions of adrenocortical hormones. In: HardmanJLimbardLGilmanA, eds. Goodman & Gilman's pharmacological basis of therapeutics. 10th ed.New York: McGraw-Hill; 2001.
29.
LuoJCShinVYLiuESYeYNWuWKSoWHChangFYChoCH.Dexamethasone delays ulcer healing by inhibition of angiogenesis in rat stomachs. Eur J Pharmacol. 2004;485 (1–3): 275–81.
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.
32.
DrachmanDESimonDI.Inflammation as a mechanism and therapeutic target for in-stent restenosis. Curr Atheroscler Rep. 2005;7 (1): 44–9.
33.
KimTKBurgessDJ.Pharmacokinetic characterization of 14C-vascular endothelial growth factor controlled release microspheres using a rat model. J Pharm Pharmacol. 2002;54 (7): 897–905.
34.
TipnisRVaddirajuSJainFBurgessDJPapadimitrakopoulosF.Layer by layer assembled semipermeable membrane for amperometric glucose sensors. J Diabetes Sci Technol. 2007;1 (2): 193–200.
35.
VaddirajuSBurgessDJainFPapadimitrakopoulosF.The role of H2O2 outer diffusion on the performance of implantable glucose sensors. Biosens Bioelectron. In press 2008.
36.
HickeyTKreutzerDBurgessDJMoussyF.Dexamethasone/PLGA microspheres for continuous delivery of an anti-inflammatory drug for implantable medical devices. Biomaterials. 2002;23 (7): 1649–56.
37.
KimTKBurgessDJ.Formulation and release characteristics of poly(lactic-co-glycolic acid) microspheres containing chemically modified protein. J Pharm Pharmacol. 2001;53 (1): 23–31.
38.
ZolnikBSBurgessDJ.Effect of acidic pH on PLGA microsphere degradation and release. J Control Release. 2007;122 (3): 338–44.
39.
ZolnikBSLearyPEBurgessDJ.Elevated temperature accelerated release testing of PLGA microspheres. J Control Release. 2006;112 (3): 293–300.
BurczakKGamianEKochmanA.Long-term in vivo performance and biocompatibility of poly(vinyl alcohol) hydrogel macrocapsules for hybrid-type artificial pancreas. Biomaterials. 1996;17 (24): 2351–6.
42.
ElçinYMDixitVGitnickG.Extensive in vivo angiogenesis following controlled release of human vascular endothelial cell growth factor: implications for tissue engineering and wound healing. Artif Organs. 2001;25 (7): 558–65.
43.
GuFAmsdenBNeufeldR.Sustained delivery of vascular endothelial growth factor with alginate beads. J Control Release. 2004;96 (3): 463–72.
44.
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.
45.
NortonLWTegnellEToporekSSReichertWM.In vitro characterization of vascular endothelial growth factor and dexamethasone releasing hydrogels for implantable probe coatings. Biomaterials. 2005;26 (16): 3285–97.
46.
NortonLWYuanFReichertWM.Glucose recovery with bare and hydrogel-coated microdialysis probes: experiment and simulation of temporal effects. Anal Chem. 2007;79 (2): 445–52.
47.
SharkawyAAKlitzmanBTruskeyGAReichertWM.Engineering the tissue which encapsulates subcutaneous implants. II. Plasma-tissue exchange properties. J Biomed Mater Res. 1998;40 (4): 586–97.
48.
SharkawyAAKlitzmanBTruskeyGAReichertWM.Engineering the tissue which encapsulates subcutaneous implants. III. Effective tissue response times. J Biomed Mater Res. 1998;40 (4): 598–605.
49.
VoskericianGShiveMSShawgoRSvon RecumHAndersonJMCimaMJLangerR.Biocompatibility and biofouling of MEMS drug delivery devices. Biomaterials. 2003;24 (11): 1959–67.
50.
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.
51.
YoonJJKimJHParkTG.Dexamethasone-releasing biodegradable polymer scaffolds fabricated by a gas-foaming/salt-leaching method. Biomaterials. 2003;24 (13): 2323–9.
52.
BurgessDJHickeyA.Microspheres: design and manufacturing. In: BurgessDJ, ed. Injectable dispersed systems: formulation, processing and performance. 1st ed.Boca Raton: Taylor & Francis; 2005.
53.
WuXS.Synthesis and properties of biodegradable lactic/glycolic acid polymers. In: WiseDLTrantoloDJAltobelliDEYaszemskiMJGresserJDSchwartzER, eds. Encyclopedic handbook of biomaterials and bioengineering. New York: Marcel Dekker; 1995.
54.
LewisDH.Controlled release of bioactive agents from lactide/glycolide polymers. In: ChassinMLangerR, eds. Biodegradable polymers as drug delivery systems. New York: Marcel Dekker; 1990.
55.
GöpferichA.Polymer degradation and erosion: mechanisms and applications. Eur J Pharm Biopharm. 1996;42 (1): 1–11.
56.
SandersJEBaleSDNeumannT.Tissue response to microfibers of different polymers: polyester, polyethylene, polylactic acid, and polyurethane. J Biomed Mater Res. 2002;62 (2): 222–7.
57.
VanceRJMillerDCThapaAHaberstrohKMWebsterTJ.Decreased fibroblast cell density on chemically degraded poly-lactic-co-glycolic acid, polyurethane, and polycaprolactone. Biomaterials. 2004;25 (11): 2095–103.
58.
ParkJ HyungBaeYH.Hydrogels based on poly(ethylene oxide) and poly(tetramethylene oxide) or poly(dimethyl siloxane). III. In vivo biocompatibility and biostability. J Biomed Mater Res A. 2003;64 (2): 309–19.
59.
SunQChenRRShenYMooneyDJRajagopalanSGrossmanPM.Sustained vascular endothelial growth factor delivery enhances angiogenesis and perfusion in ischemic hind limb. Pharm Res. 2005;22 (7): 1110–6.
60.
VermaJNRaoMAmselemSKrzychUAlvingCRGreenSJWassefNM.Adjuvant effects of liposomes containing lipid A: enhancement of liposomal antigen presentation and recruitment of macrophages. Infect Immun. 1992;60 (6): 2438–44.
61.
TomiyaNWatanabeKAwayaJKuronoMFujiiS.Modification of acyl-plasmin-streptokinase complex with polyethylene glycol. Reduction of sensitivity to neutralizing antibody. FEBS Lett. 1985;193 (1): 44–8.
62.
CohenSYoshiokaTLucarelliMHwangLHLangerR.Controlled delivery systems for proteins based on poly(lactic/glycolic acid) microspheres. Pharm Res. 1991;8 (6): 713–20.
63.
HalkinAStoneGW.Polymer-based paclitaxel-eluting stents in percutaneous coronary intervention: a review of the TAXUS trials. J Interv Cardiol. 2004;17 (5): 271–82.
64.
LiJJLiJNanJLLiZZhenXMuCWDaiJZhangCY.Coronary restenotic reduction of drug-eluting stenting may be due to its anti-inflammatory effects. Med Hypotheses. 2007;69 (5): 1004–9.
65.
LincoffAMFurstJGEllisSGTuchRJTopolEJ.Sustained local delivery of dexamethasone by a novel intravascular eluting stent to prevent restenosis in the porcine coronary injury model. J Am Coll Cardiol. 1997;29 (4): 808–16.
66.
SuzukiTKopiaGHayashiSBaileyLRLlanosGWilenskyRKlugherzBDPapandreouGNarayanPLeonMBYeungATioFTsaoPSFaloticoRCarterAJ.Stent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model. Circulation. 2001;104 (10): 1188–93.
67.
CasconeM GraziaZhuZBorselliFLazzeriL.Poly(vinyl alcohol) hydrogels as hydrophilic matrices for the release of lipophilic drugs loaded in PLGA nanoparticles. J Mater Sci Mater Med. 2002;13 (1): 29–32.
68.
HassanCMStewartJEPeppasNA.Diffusional characteristics of freeze/thawed poly(vinyl alcohol) hydrogels: applications to protein controlled release from multilaminate devices. Eur J Pharm Biopharm. 2000;49 (2): 161–5.
69.
WillcoxPJHowieDWJrSchmidt-RohrKHoaglandDAGidoSPudjijantoSKleinerLVenkatramanS.Microstructure of poly(vinyl alcohol) hydrogels produced by freeze/thaw cycling. J Polym Sci Part B: Polym Phys. 1999;37 (24): 3438–54.
70.
HassanCMPeppasNA.Structure and applications of poly(vinyl alcohol) hydrogels produced by conventional cross-linking or by freezing/thawing methods. Adv Polym Sci. 2000;153: 37–65.
