The purpose of this study was to describe the cellular architecture of normal human peripapillary sclera (PPS) and evaluate surface topography's role in fibroblast behavior. METHODS.PPS cryosections from nonglaucomatous eyes were labelled for nuclei, fibrillar actin (FA), and alpha smooth muscle actin (αSMA) and imaged. Collagen fibrils were imaged using second harmonic generation. Nuclear density and aspect ratio of the internal PPS (iPPS), outer PPS (oPPS), and peripheral sclera were determined. FA and αSMA fibril alignment with collagen extracellular matrix (ECM) was determined. PPS fibroblasts were cultured on smooth or patterned membranes under mechanical strain and in the presence of TGFβ1 and 2. RESULTS.The iPPS (7.1 ± 2.0 × 10 −4 , P < 0.0001) and oPPS (5.3 ± 1.4 × 10 −4 , P = 0.0013) had greater nuclei density (nuclei/μm 2 ) than peripheral sclera (2.5 ± 0.8 × 10 −4 ). The iPPS (2.0 ± 0.3, P = 0.002) but not oPPS (2.4 ± 0.4, P = 0.45) nuclei had smaller aspect ratios than peripheral (2.7 ± 0.5) nuclei. FA was present throughout the scleral stroma and was more aligned with oPPS collagen (9.6 ± 1.9 degrees) than in the peripheral sclera (15.9 ± 3.9 degrees, P =0.002). The αSMA fibers in the peripheral sclera were less aligned with collagen fibrils (26.4 ± 4.8 degrees) than were FA (15.9 ± 3.9 degrees, P = 0.0002). PPS fibroblasts cultured on smooth membranes shifted to an orientation perpendicular to the direction of cyclic uniaxial strain (1 Hz, 5% strain, 42.2 ± 7.1 degrees versus 62.0 ± 8.5 degrees, P < 0.0001), whereas aligned fibroblasts on patterned membranes were resistant to strain-induced reorientation (5.9 ± 1.4 degrees versus 10 ± 3.3 degrees, P = 0.21). Resistance to re-orientation was reduced by TGFβ treatment (10 ± 3.3 degrees without TGFβ1 compared to 23.1 ± 4.5 degrees with TGFβ1, P < 0.0001). CONCLUSIONS.Regions of the posterior sclera differ in cellular density and nuclear morphology. Topography alters the cellular response to mechanical strain.

Biomaterials are implanted in millions of individuals worldwide each year. Both naturally derived and synthetic biomaterials induce a foreign body reaction that often culminates in fibrotic encapsulation and reduced functional lifespan. In ophthalmology, glaucoma drainage implants (GDIs) are implanted in the eye to reduce intraocular pressure (IOP) in order to prevent glaucoma progression and vision loss. Despite recent efforts towards miniaturization and surface chemistry modification, clinically available GDIs are susceptible to high rates of fibrosis and surgical failure. Here, we describe the development of synthetic, nanofiber‐based GDIs with partially degradable inner cores. We evaluated GDIs with nanofiber or smooth surfaces to investigate the effect of surface topography on implant performance. We observed in vitro that nanofiber surfaces supported fibroblast integration and quiescence, even in the presence of pro‐fibrotic signals, compared to smooth surfaces. In rabbit eyes, GDIs with a nanofiber architecture were biocompatible, prevented hypotony, and provided a volumetric aqueous outflow comparable to commercially available GDIs, though with significantly reduced fibrotic encapsulation and expression of key fibrotic markers in the surrounding tissue. We propose that the physical cues provided by the surface of the nanofiber‐based GDIs mimic healthy extracellular matrix structure, mitigating fibroblast activation and potentially extending functional GDI lifespan.

Quorum sensing (QS) antagonists have been proposed as novel therapeutic agents to combat bacterial infections. We previously reported that the secondary metabolite 3-methyl-N-(2′-phenylethyl)-butyramide, produced by a marine bacterium identified as Halobacillus salinus, inhibits QS controlled phenotypes in multiple Gram-negative reporter strains. Here we report that N-phenethyl hexanamide, a structurally-related compound produced by the marine bacterium Vibrio neptunius, similarly demonstrates QS inhibitory properties. To more fully explore structure–activity relationships within this new class of QS inhibitors, a panel of twenty analogs was synthesized and biologically evaluated. Several compounds were identified with increased attenuation of QS-regulated phenotypes, most notably N-(4-fluorophenyl)-3-phenylpropanamide against the marine pathogen Vibrio harveyi (IC50 = 1.1 µM). These findings support the opportunity to further develop substituted phenethylamides as QS inhibitors.