Morphology and mechanisms of endogenous cell-mediated remodeling of heart valves fabricated from a novel restorative polymer: Comparison of pulmonary vs aortic valves implanted in sheep for up to one year


Background

Endogenous Tissue Restoration (ETR) is a regenerative approach in which synthetic, polymeric implants induce functional tissue formation mediated by endogenous cells, without preimplantation cell seeding or chemical adjuncts. This study evaluated the structural evolution of pulmonary and aortic valves composed of a polymer designed to undergo ETR.


Materials and Methods

Prior work demonstrated that pulmonary arterial and aortic conduits fabricated from a family of restorative supramolecular polymers based on the self-complementary ureido-pyrimidinone (UPy) quadruple hydrogen-bonding motif had patency and progressive load bearing by new tissue for up to one year in sheep. Herein, we report studies of heart valves of multiple UPy- compositions surgically implanted into adult sheep for 3, 6 and 12 months. Groups included pulmonary valved conduits (PV, n=18) and orthotopic aortic valves (AV) implanted via an open transapical (n=46) approach. Angiography and ultrasound evaluated in-vivo functionality. Explanted specimen mechanical properties were measured and morphologic examinations were performed.


Results

Overall, 15 of 18 PV and 8, 15, and 14 AV functioned to 3, 6 and 12 months, respectively, with mild progressive stiffening, regurgitation and some degenerative changes. Most AV and PV were structurally intact at sacrifice; however, a small minority of PV and AV had partial cuspal tears and/or focal calcification. Histological features of remodeling were qualitatively similar in PV and AV, and across UPy formulations. Morphologic examination demonstrated ongoing intimal thickening, variable focal inflammation, less in later implants, progressive polymer absorption, and fibrous tissue replacement, beginning early and ongoing at 12-months in both PV and AV. Correlation of morphology with design features and absorption data suggests that structural defects result from focally excessive polymer strength loss, combined with inadequate tissue formation, and superimposed mechanical factors.


Conclusions

These studies demonstrate the structural evolution of polymer absorption, ETR and remodeling of PV and AV in sheep to one year, with mechanisms and morphologic features consistent across configurations and sites. Thus, initially cell-free synthetic bioabsorbable implants can guide the restoration of host tissue into functional valvular replacements. Nevertheless, polymer absorption rates will need to be optimally balanced with tissue synthesis and remodeling to provide consistently optimal outcomes.