Pirfenidone Delivery by Blow-Molded PCL Nanofiber Mat to Reduce Collagen Synthesis by Fibroblasts

Abstract

Elevated intraocular pressure (IOP) during glaucoma is sometimes mitigated by insertion of glaucoma drainage devices (GDD). Excessive fibrosis around GDD plates may confine drainage and requiring revision surgeries in some patients. Pirfenidone (PFD) is an FDA approved drug to treat lung fibrosis, and it may be effective in limiting capsule formation around the GDD. To enable this, we aimed to develop a polymeric GDD encasement sheath that can sustainably release PFD to reduce fibrous capsule formation. The PFD-doped sheath was manufactured by blow molding of (poly)caprolactone (PCL). We investigated the effects of PCL concentration, spray distance, and molecular weight on the morphology of nanofibers as well as the release rate of PFD. The effects of PFD delivery on viability, number of living cells and collagen production by L-929 fibroblasts were measured in vitro. It was found that concentrations of 6%, 8%, and 10% PCL resulted in average fiber diameters of 277 ± 134, 436 ± 176, and 689 ± 297 nm, respectively. With increasing fiber diameter, the blow-spun nanofiber matrix displayed reduced burst release of PFD; ~75%, ~60%, and 45% respectively. Lower molecular weight PCL (25 kDa) demonstrated a slower release than higher molecular weight PCL (80 kDa). PCL loaded with PFD reduced collagen synthesis by L929 fibroblasts in vitro. The materials were also placed in a preliminary capacity as a proof of concept in the extraorbital space in rabbits and scored histologically to infer the severity of the inflammatory reaction. Assessment of in vivo response to blow-spun nanofibrous forms of PCL indicated a notably high inflammatory reaction to PCL. Therefore, while PFD can be integrated in PCL during blow-spinning and demonstrates antifibrotic effect in vitro, in vivo response to nanofibrous PCL by and itself suggests that this material platform does not appear to be suitable for drug delivery in the extraocular milieu.