Controlled release of low-molecular weight, polymer-free corticosteroid coatings suppresses fibrotic encapsulation of implanted medical devices.

Inflammation-driven foreign body reactions, and the frequently associated encapsulation by fibrogenic fibroblasts, reduce the functionality and longevity of implanted medical devices and materials. Anti-inflammatory drugs, such as dexamethasone, can suppress the foreign body reaction for a few days post-surgery, but lasting drug delivery strategies for long-term implanted materials remain an unmet need. We here establish a thin-coating strategy with novel low molecular weight corticosteroid dimers to suppress foreign body reactions and fibrotic encapsulation of subcutaneous silicone implants. The dimer coatings are >75% dexamethasone by mass and directly processable into conformal coatings using conventional solvent-based techniques, such as casting or spray coating without added polymers or binding agents. In vitro, surface erosion of the coating, and subsequent hydrolysis, provide controlled release of free dexamethasone. In a rat subcutaneous implantation model, the resulting slow and sustained release profile of dexamethasone is effective at reducing the number and activation of pro-fibrotic macrophages both acutely and at chronic time points. Consequently, fibroblast activation, collagen deposition and fibrotic encapsulation are suppressed at least 45 days post-implantation. Thus, our approach to protect implants from host rejection is advantageous over polymeric drug delivery systems, which typically have low drug loading capacity (<30%), initial burst release profiles, and unpredictable release kinetics.

Macroporous photocrosslinked elastomer scaffolds containing microposity: preparation and in vitro degradation properties.

The engineering of soft tissue would benefit from the development of effective biodegradable scaffolds capable of dynamic, elastic loading. For this purpose, highly porous, elastomeric scaffolds containing microporous struts were prepared using a dual porogen approach and a photocrosslinkable elastomer. The combination of paraffin microbeads distributed through a water-in-[star-poly(lactide-co-epsilon-caprolactone) triacrylate dissolved in ethyl acetate] emulsion followed by photocrosslinking generated a macroporous foam scaffold of average porosities between 90% to 93%, with an average pore diameter of 104 +/- 31 microm with struts containing micropores of 3.1 +/- 2 microm average diameter. The mechanical properties of the scaffolds were readily manipulatable by altering the molecular weight of the star-poly(lactide-co-epsilon-caprolactone) triacrylate prepolymer used. The elastomer scaffolds degraded at the same rate as nonporous polymer samples of the same molecular weight, and exhibited similar changes in mass loss, mechanical properties, and sol fraction during in vitro degradation as found with the nonporous scaffolds. The modulus and stress at break of the scaffolds decreased continuously during degradation while the strain at break remained constant. These scaffolds show potential for use in the engineering of soft tissues.

Surface modifications of photocrosslinked biodegradable elastomers and their influence on smooth muscle cell adhesion and proliferation.

Photocrosslinked, biodegradable elastomers based on aliphatic polyesters have many desirable features as scaffolds for smooth muscle tissue engineering. However, they lack cell adhesion motifs. To address this shortcoming, two different modification procedures were studied utilizing a high and a low crosslink density elastomer: base etching and the incorporation of acryloyl-poly(ethylene glycol) (PEG)-Gly-Arg-Gly-Asp-Ser (GRGDS) into the elastomer network during photocrosslinking. Base etching improved surface hydrophilicity without altering surface topography, but did not improve bovine aortic smooth muscle cell adhesion. Incorporation of PEG-GRGDS into the elastomer network significantly improved cell adhesion for both high and low crosslink density elastomers, with a greater effect with the higher crosslink density elastomer. Incorporation of GRGDS into the high crosslink density elastomer also enhanced smooth muscle cell proliferation, while proliferation on the low crosslink density unmodified, base etched, and PEG-GRGDS incorporated elastomers was significantly greater than on the high crosslink density unmodified and base etched elastomer.