Pyriphenone modification of glutaraldehyde pretreated bovine pericardium mitigates advanced glycation end products, calcification, and platelet adhesion

Heterograft biomaterials, such as glutaraldehyde-pretreated bovine pericardium (BP), are used to fabricate bioprosthetic heart valves (BHV). BHV durability is limited by structural valve degeneration (SVD), which is caused by either advanced glycation end products (AGE) with associated serum protein deposition, calcification, or both. Vitamin B6 vitamers have been investigated experimentally and clinically for mitigating AGE formation that complicates diabetes. In the present study, we investigated a vitamin B6-based photo-responsive molecule, Pyriphenone (PPh), hypothesizing that PPh could mitigate both BP AGE-serum protein uptake and BP calcification in vivo. PPh was synthesized by reacting pyridoxamine with benzophenone. PPh was optimally soluble in ethanol, and PPh-ethanol solutions were used for all PPh studies. PPh was demonstrated to become covalently and stably attached to BP with exposure to ultraviolet light. PPh-BP demonstrated significantly reduced in vitro AGE deposition and associated serum albumin uptake, versus unmodified BP. PPh-BP showed significant resistance to oxidation in vitro and demonstrated comparable biaxial mechanical properties to unmodified BP. In vitro hydrodynamic testing of trileaflet BHV fabricated from BP-PPh demonstrated no alterations of functionality, compared to unmodified BHV. In vivo 28-day subdermal implants in juvenile rats with either PPh-BP or unmodified BP demonstrated that PPh significantly mitigated AGE and serum albumin uptake, and calcification versus unmodified BP. Ex vivo studies of BP-PPh exposed to human whole blood demonstrated significantly reduced adhesion of platelets and white blood cells versus unmodified BP. In conclusion, PPh-BP mitigates calcification, AGE, and serum albumin uptake and reduces platelet and white blood cell adhesion. STATEMENT OF SIGNIFICANCE: Heart valve disease is highly prevalent, affecting millions. At this time, it can only be treated by either surgical valve repair or replacement of the diseased valve with a prosthesis. Bioprosthetic heart valves, fabricated from heterograft materials, are the most widely used heart valve replacements. However, these devices have poor durability due to calcification and advanced glycation end-product (AGE) deposition, which cause structural valve degeneration. Pyriphenone, the subject of this paper, is a compound synthesized by the authors that is shown in this paper to confer resistance to bioprosthetic valve calcification and AGE deposition.