Polymer anchors with responsive heparin release for the anticoagulant decoration of hemodialysis membranes

Introduction Extracorporeal hemodialysis is a standard treatment of terminal renal insufficiency. The intense contact of blood with the dialysis membrane requires systemic anticoagulation, associated with bleeding risks and side effects. Surface modifications for improved hemocompatibility are requested that allow reduced systemic anticoagulation.

Method Styrene-maleic acid anhydride copolymers were systematically conjugated with poly(ethylene glycol) (PEG) to form amphiphilic polymer anchors that adsorb to the surface from aqueous solution. The anticoagulant heparin was functionalized to an anchor polymer-PEG conjugate or directly to the polymer backbone. The system was extended for feedback-control properties by heparin-anchor polymer conjugation via a linker peptide, which is selectively cleaved by the coagulation factor thrombin ([Fig. 1]).

Fig. 1  Scheme of the anchor polymer structure and adsorption to the membrane.

Anchor polymer-heparin conjugates were analysed for their adsorption on PES surfaces and PES/PVP membranes. Besides, the thrombin responsive heparin release and the anticoagulant effect of the coating were tested in a buffer system and recalcified citrate plasma.

Results Anchor polymers formed a homogeneous and stable coating on a PES film in an aqueous solution, with tunable density by modification of the PEG:Styrene ratio and the molecular weight of the PEG. Still, removal was possible by a detergent or by self-replacement, allowing regeneration of the coating [1].

Heparin conjugation had only minor effects on the adsorption characteristics of the anchor polymer. The heparin surface density on hemodialysis membranes was comparable to established heparinized products. Thrombin-antithrombin complex formation on coated hollow fibers proved the catalytic activity of the immobilized heparin.

The heparin release by thrombin substantially delayed plasma coagulation compared to stable immobilization; however, there was high variation between different peptides ([Fig. 2]).

Fig. 2  Coagulation time of citrate plasma on coated flat membranes.

Conclusion Anchor polymers present a versatile method for the biofunctionalization of polymer surfaces such as hemodialysis membranes from aqueous solutions. The integration of selectively cleavable linker peptides allows for the formation of feedback-controlled responsive systems. The modular set-up of the anchor polymers provides flexibility to exchange and combine drugs with different functionality.

Publikationsverlauf

Artikel online veröffentlicht:
20. Februar 2023

• References

• 1 Ruland A, Schenker S, Schirmer L, Friedrichs J, Meinhardt A, Schwartz VB, Kaiser N, Konradi R, MacDonald W, Helmecke T, Sikosana MKLN, Valtin J, Hahn D, Renner LD, Werner C, Freudenberg U. 'Amphiphilic copolymers for versatile, facile, and in situ tunable surface biofunctionalization'. Adv. Mater 2021; 2002489