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, presents 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 PBS buffer led to a monotonic increase in glucose permeability (50%), with a corresponding enhancement in sensor sensitivity over a one-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 two-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.

Fabrication of extended-release patient-tailored prednisolone tablets via fused deposition modelling (FDM) 3D printing

“…by an erosion mechanism(Vaddiraju et al, 2012; Westedt et al3D printing was adapted to engineer and control the379 dose of extended release tablets. Prednisolone loaded PVA filament 380 demonstrated the ability to be printed into ellipse shaped tablets 381 using 3D printer.…”

Macroscopic porosity generation in outer hydrogel membranes to offset sensitivity loss in implantable glucose sensors

“…The constant decrease in sensor sensitivity is due to reduction in glucose flux through the PVA coatings (days 1-6) as well as through the inner sensory membranes (days 7-30). [19] In the case of composite membranes (Figure 5b), the glucose flux showed phases of increments and decrements over the entire 30-day incubation period. The initial increase (days 1-3) in glucose flux could be due to dislodging of smaller microspheres from the surface in the viscous serum solution as well as due to dexamethasone burst release from the microsphere surface [19].…”

“…[19] In brief, PVA membranes (with and without PLGA microspheres) were sandwiched between the donor and receiver chambers of the Franz cell that contained 1M and 5.6 mM glucose solutions, respectively. The amount of glucose diffused from the donor to the receiver chamber through the membrane has been quantified as function of time.…”

Preclinical Performance Evaluation of Percutaneous Glucose Biosensors

“…In addition to sufficient stability and the ability to resist the FBR, these external coatings must not diminish the analytical performance of the sensor. Benchtop sensor-material compatibility studies, [7][8][9] FBR models, [10][11] and in vivo histological and immunohistochemical analysis [12][13] are all used to evaluate the potential benefits of new sensor materials to device performance ( Figure 1). Despite the utility of these tests for examining biocompatibility, a distinct correlation between in vitro or histological observations and actual sensor function is lacking in biomaterials literature.…”