title: Microsphere erosion in outer hydrogel membranes creating macroscopic porosity to counter biofouling-induced sensor degradation.
abstract: Biofouling and tissue inflammation present major challenges toward the realization of long-term implantable glucose sensors. Following sensor implantation, proteins and cells adsorb on sensor surfaces to not only inhibit glucose flux but also signal a cascade of inflammatory events that eventually lead to permeability-reducing fibrotic encapsulation. The use of drug-eluting hydrogels as outer sensor coatings has shown considerable promise to mitigate these problems via the localized delivery of tissue response modifiers to suppress inflammation and fibrosis, along with reducing protein and cell absorption. Biodegradable poly (lactic-co-glycolic) acid (PLGA) microspheres, encapsulated within a poly (vinyl alcohol) (PVA) hydrogel matrix, present a model coating where the localized delivery of the potent anti-inflammatory drug dexamethasone has been shown to suppress inflammation over a period of 1-3 months. Here, it is shown that the degradation of the PLGA microspheres provides an auxiliary venue to offset the negative effects of protein adsorption. This was realized by: (1) the creation of fresh porosity within the PVA hydrogel following microsphere degradation (which is sustained until the complete microsphere degradation) and (2) rigidification of the PVA hydrogel to prevent its complete collapse onto the newly created void space. Incubation of the coated sensors in phosphate buffered saline (PBS) led to a monotonic increase in glucose permeability (50%), with a corresponding enhancement in sensor sensitivity over a 1 month period. Incubation in serum resulted in biofouling and consequent clogging of the hydrogel microporosity. This, however, was partially offset by the generated macroscopic porosity following microsphere degradation. As a result of this, a 2-fold recovery in sensor sensitivity for devices with microsphere/hydrogel composite coatings was observed as opposed to similar devices with blank hydrogel coatings. These findings suggest that the use of macroscopic porosity can reduce sensitivity drifts resulting from biofouling, and this can be achieved synergistically with current efforts to mitigate negative tissue responses through localized and sustained drug delivery.
authors.affiliation: Polymer Program, Institute of Materials Science, University of Connecticut, Storrs, CT 06269-3136.|Biorasis Inc. Technology Incubation Program, University of Connecticut, Storrs, CT 06269-4213.
authors.forename: S
authors.initials: S
authors.lastname: Vaddiraju
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Polymer Program, Institute of Materials Science, University of Connecticut, Storrs, CT 06269-3136.
authors.forename: L
authors.initials: L
authors.lastname: Qiang
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092.
authors.forename: D J
authors.initials: DJ
authors.lastname: Burgess
authors.affiliation: Polymer Program, Institute of Materials Science, University of Connecticut, Storrs, CT 06269-3136.|Department of Chemistry, University of Connecticut, Storrs, CT 06269-3060.
authors.forename: F
authors.initials: F
authors.lastname: Papadimitrakopoulos
mesh_terms: D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D057219:Biofouling / Q000517:prevention & control*; D015374:Biosensing Techniques / Q000295:instrumentation*; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000378:metabolism*; D003907:Dexamethasone / Q000008:administration & dosage*; D005947:Glucose / Q000032:analysis* / Q000378:metabolism; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008863:Microspheres; D010539:Permeability; D011100:Polyglycolic Acid / Q000378:metabolism; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011142:Polyvinyl Alcohol / Q000737:chemistry / Q000378:metabolism; D016062:Porosity; D012680:Sensitivity and Specificity
chemical_list: D000893:Anti-Inflammatory Agents; D003692:Delayed-Action Preparations; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D011100:Polyglycolic Acid; D019344:Lactic Acid; D003907:Dexamethasone; D011142:Polyvinyl Alcohol; D005947:Glucose