Poly-2-methyl-2-oxazoline–modified bioprosthetic heart valve leaflets have enhanced biocompatibility and resist structural degeneration

Abstract

Bioprosthetic heart valves (BHV) fabricated from glutaraldehyde-fixed heterograft tissue, such as bovine pericardium (BP), are widely used for treating heart valve disease, a group of disorders that affects millions. Structural valve degeneration (SVD) of BHV due to both calcification and the accumulation of advanced glycation end products (AGE) with associated serum proteins limits durability. We hypothesized that BP modified with poly-2-methyl-2-oxazoline (POZ) to inhibit protein entry would demonstrate reduced accumulation of AGE and serum proteins, mitigating SVD. In vitro studies of POZ-modified BP demonstrated reduced accumulation of serum albumin and AGE. BP-POZ in vitro maintained collagen microarchitecture per two-photon microscopy despite AGE incubation, and in cell culture studies was associated with no change in tumor necrosis factor-α after exposure to AGE and activated macrophages. Comparing POZ and polyethylene glycol (PEG)–modified BP in vitro, BP-POZ was minimally affected by oxidative conditions, whereas BP-PEG was susceptible to oxidative deterioration. In juvenile rat subdermal implants, BP-POZ demonstrated reduced AGE formation and serum albumin infiltration, while calcification was not inhibited. However, BP-POZ rat subdermal implants with ethanol pretreatment demonstrated inhibition of both AGE accumulation and calcification. Ex vivo laminar flow studies with human blood demonstrated BP-POZ enhanced thromboresistance with reduced white blood cell accumulation. We conclude that SVD associated with AGE and serum protein accumulation can be mitigated through POZ functionalization that both enhances biocompatibility and facilitates ethanol pretreatment inhibition of BP calcification.

Conformational Parameters and Hydrodynamic Behavior of Poly(2-Methyl-2-Oxazoline) in a Broad Molar Mass Range

“…To date, PEtOx appears to be the most investigated poly(2-oxazoline) in terms of biomedical applications [ 7 , 10 , 14 , 15 , 16 , 27 ], and PEtOx based polymer-drug conjugates and hemostatic materials have also reached human clinical trials [ 28 , 29 , 30 , 31 ]. Nonetheless, PMeOx is an important runner-up, and is especially attractive to shield drug carriers and for antifouling coatings based on its hydrophilicity, which is higher than that of PEtOx and PEG [ 17 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. It was shown that more hydrophilic PMeOx exhibits better anti-fouling properties than both PEtOx with longer side chains and PEG [ 32 , 33 , 34 , 35 , 36 , 37 , 38 ], and allows higher hydrophobic drug loading [ 32 ].…”

“…While comparing particular therapeutically significant properties, thiolated silica nanoparticles functionalized with PMeOx were shown to be considerably more penetrating through mucosal tissue than particles functionalized with PEtOx or poly-(2-n-propyl-2-oxazoline)s [ 39 ]. Another recent study showed that modification of bovine pericardium-based bioprosthetic heart valves with PMeOx creates a biocompatible surface that demonstrated enhanced resistance to serum protein infiltration and glycation and better thromboresistance compared to the PEG-modified version [ 40 ].…”

Preparation of Alginic Acid/Poly(2‐Oxazoline) Hybrid Gels and Their Use in Cell Preservation

“…Poly(2-oxazoline)s, pseudopeptides having pendent amido groups, are synthesized via ring-opening polymerization of 2-oxazoline [37][38][39][40][41][42][43][44][45][46][47] and are known to show excellent biocompatibility. [48][49][50][51][52][53][54][55][56] We have already reported incorporation of poly(2-oxazoline)s into biosynthesized artificial extracellular matrix protein (CS5-ELF) consisting of a REDV sequence in the cell-binding domain and an elastin-like sequence. [57][58][59][60] The side chain introduction of poly(ethylene oxide), [59] poly(2-oxazoline)s, [58] and poly(NIPAM), [60] enabled us to control both the lower critical solution temperature (LCST) and cell detachment from a surface.…”

Bioprosthetic heart valve structural degeneration associated with metabolic syndrome: Mitigation with polyoxazoline modification

“…Despite these findings, mechanisms of SVD remain under continued study. Several works have implicated the degeneration of the extracellular matrix (ECM) and fibrocalcific remodeling by dystrophic calcification as major contributors to the pathogenesis of SVD ( 9 , 13 – 20 ).…”

“…Given the role of circulating protein infiltration in initiating and directing BHV leaflet degeneration, we formulated and characterized a BHV biomaterial modified with poly-2-methyl-2-oxazoline (POZ) ( 19 ) aimed at reducing protein absorption. POZ is a novel compound in a class of antifouling polymers that blocks protein infiltration and resists oxidative stress.…”