Biocompatibility of a novel lung sealant based on functionalized polyoxazolines in an ovine model of parenchymal lung injury.

Abstract

Background: A lung sealant based on a porcine gelatin carrier impregnated with N-hydroxysuccinimide ester functionalized poly(2)oxazolines (NHS-POx) and nucleophilically activated polyoxazolines (NU-POx) was shown to be efficacious for lung sealing ex-vivo and in-vivo. In the current study, we investigated the local biocompatibility by assessing inflammation, healing, and biodegradability in an ovine model of superficial parenchymal lung injury.

Methods: Three groups, NHS-POx, fibrin patch (TachoSil^®) and untreated control, are randomly applied to superficial lesions (3 mm depth) on the right lung (n=3/lung) of adult female domestic sheep, which are sacrificed for blinded histological assessment at 5, 14, and 42 days (n=4 animals per term). Semi-quantitative scoring (scale 0-4) was performed on immune cell subtypes (polymorphonuclear cells, lymphocytes, plasma cells, macrophages, giant cells, necrosis) and biomaterial response (fibrosis, neovascularization, fatty infiltrate). Post-hoc analysis was performed for a suspected labeling mistake and adapted datasets were obtained (6 weeks).

Results: The total cell response score was significantly higher for NHS-POx vs. control [score: 11.5 (range, 9-13) vs. 7 (range, 6-8), P=0.005] at 5 days, and for fibrin patch vs. control [score: 14 (range, 12-17) vs. 7 (range, 5-8), P=0.02] at 2 weeks. At 6 weeks, cell response was similar between groups (P=0.22), with outliers due to granulomatous inflammation to residual patch (n=1 fibrin patch and n=1 mix-up sample likely fibrin patch). Wound healing, fibrosis, and neovascularization were similar across groups, showing local pleural thickening. NHS-POx patch showed mesothelial coverage at 2 weeks and was macro- and microscopically completely degraded at 6 weeks with replacement of the patch material with extracellular matrix (adapted data).

Conclusions: The NHS-POx patch shows a comparable to favorable biocompatibility profile compared to fibrin patch, and is a potent candidate for clinical lung sealing applications.