The role of carboxylic groups in heparin-mimicking polymer-functionalized surfaces for blood compatibility: Enhanced vascular cell selectivity.

Blood compatibility is an eternal topic of biomedical materials. The effect of heparin-mimicking polymers (HMPs) on blood compatibility has been well studied, especially the synergistic effect of sugar unit and sulfonate/sulfate unit. However, carboxylic groups also play an important role in HMPs. In this work, copolymers of sodium 4-vinyl-benzenesulfonate (SS) and 2-methacrylamido glucopyranose (MAG) (poly(SS-co-MAG)) and poly(acrylate acid) (PAA) were self-assembled on Au surfaces with different feed ratios. When self-assembly of poly(SS-co-MAG) alone, the optimized feed ratio of SS and MAG for vascular cell selectivity was 1:1 (PS1M1); at this ratio the Au-PS1M1 surface showed the highest human umbilical vein endothelial cells (HUVECs) density and the lowest human umbilical vein smooth muscle cells (HUVSMCs) density. When self-assembly of PAA alone (surface designated as Au-PAA), the proliferation of both HUVECs and HUVSMCs was inhibited. Compared with either PS1M1 or PAA alone, the surfaces modified with both PAA and PS1M1 at the feed ratio of 1:1 (material designated as Au-PSM/PAA-2) showed enhanced promoting effect on HUVECs as well as enhanced inhibiting effect on HUVSMCs, indicating stronger vascular cell selectivity of carboxylic groups in the presence of sugar and sulfonate units.

Nitric Oxide-Generating Antiplatelet Polyurethane Surfaces with Multiple Additional Biofunctions via Cyclodextrin-Based Host-Guest Interactions.

A nitric oxide-generating polymeric coating was prepared by copolymerization of the hydrophilic monomer 2-hydroxyethyl methacrylate (HEMA) and the comonomer 1-adamantan-1-ylmethyl methacrylate (AdaMA) with subsequent incorporation of selenocystamine. The coating was applied to polyurethane (PU) as a substrate. In the presence of a NO donor, the PU-PHA-Se surface generated nitric oxide (NO). This surface was shown to inhibit platelet adhesion and human umbilical vein smooth muscle cell adhesion and proliferation. The poly(AdaMA) on the modified surface was designed to allow the incorporation of functional units into the PU-PHA-Se surface via host-guest interactions between the adamantane groups and cyclodextrin (CD) derivatives. In this work, two functional CD complexes containing lysine (CD-L) and sulfonate (CD-S) groups were incorporated into the PU-PHA-Se surface. CD-L conferred fibrinolytic activity, whereas CD-S promoted human umbilical vein endothelial cell proliferation. This NO-generating antiplatelet polymeric coating has potential as a platform for modifying surfaces with multiple additional biological functions via host-guest interactions, thus providing an alternative approach for the preparation of biomaterials with multifunctionality.

A facile method to prepare a versatile surface coating with fibrinolytic activity, vascular cell selectivity and antibacterial properties.

Clot and thrombus formation on surfaces that come into contact with blood is still the most serious problem for blood contacting devices. Despite many years of continuous efforts in developing hemocompatible materials, it is still of great interest to develop multifunctional materials to enable vascular cell selectivity (to favor rapid endothelialization while inhibiting smooth muscle cell proliferation) and improve hemocompatibility. In addition, biomaterial-associated infections also cause the failure of biomedical implants and devices. However, it remains a challenging task to design materials that are multifunctional, since one of their functions will usually be compromised by the introduction of another function. In the present work, the gold substrate was first layer-by-layer (LbL) deposited with a multilayered polyelectrolyte film containing chitosan (positively charged) and a copolymer of sodium 4-vinylbenzenesulfonate (SS) and the "guest" adamantane monomer 1-adamantan-1-ylmethyl methacrylate (P(SS-co-Ada), negatively charged) via electro-static interactions, referred to as Au-LbL. The chitosan and P(SS-co-Ada) were intended to provide, respectively, resistance to bacteria and heparin-like properties. Then, "host" ß-cyclodextrin derivatives bearing seven lysine ligands (CD-L) were immobilized on the Au-LbL surface by host-guest interactions between adamantane residues and CD-L, referred to as Au-LbL/CD-L. Finally, a versatile surface coating with fibrinolytic activity (lysis of nascent clots), vascular cell selectivity and antibacterial properties was developed.

Sulfonate Groups and Saccharides as Essential Structural Elements in Heparin-Mimicking Polymers Used as Surface Modifiers: Optimization of Relative Contents for Antithrombogenic Properties.

Blood compatibility is a long sought-after goal in biomaterials research, but remains an elusive one, and in spite of extensive work in this area, there is still no definitive information on the relationship between material properties and blood responses such as coagulation and thrombus formation. Materials modified with heparin-mimicking polymers have shown promise and indeed may be seen as comparable to materials modified with heparin itself. In this work, heparin was conceptualized as consisting of two major structural elements: saccharide- and sulfonate-containing units, and polymers based on this concept were developed. Copolymers of 2-methacrylamido glucopyranose, containing saccharide groups, and sodium 4-vinylbenzenesulfonate, containing sulfonate groups, were graft-polymerized on vinyl-functionalized polyurethane (PU) surfaces by free radical polymerization. This graft polymerization method is simple, and the saccharide and sulfonate contents are tunable by regulating the feed ratio of the monomers. Homopolymer-grafted materials, containing only sulfonate or saccharide groups, showed different effects on cell-surface interactions including platelet adhesion, adhesion and proliferation of vascular endothelial cells, and adhesion and proliferation of smooth muscle cells. The copolymer-grafted materials showed effects due to both sulfonate and saccharide elements with respect to blood responses, and the optimum composition was obtained at a 2:1 ratio of sulfonate to saccharide units (material designated as PU-PS1M1). In cell adhesion experiments, this material showed the lowest platelet and human umbilical vein smooth muscle cell density and the highest human umbilical vein endothelial cell density. Among the materials investigated, PU-PS1M1 also had the longest plasma clotting time. This material was thus shown to be multifunctional with a combination of properties, suggesting thromboresistant behavior in blood contact.

A multifunctional surface for blood contact with fibrinolytic activity, ability to promote endothelial cell adhesion and inhibit smooth muscle cell adhesion.

Blood compatible materials are required for a wide variety of medical devices. Despite many years of intensive effort, however, the blood compatibility problem, in particular the ability to prevent thrombosis, remains unsolved. Based on the knowledge that the vascular endothelium, the ultimate blood contacting surface, draws on several mechanisms to maintain blood fluidity, it seems reasonable that analogous multifunctionality should be the goal for blood compatible biomaterials. In the present work, a polyurethane surface was modified with the terpolymer poly(2-hydroxyethyl methacrylate-co-6-amino-2-(2-methacylamido)-hexanoic acid-co-1-adamantan-1-ylmethyl methacrylate) (poly(HEMA-co-LysMA-co-AdaMA)), referred to as PU-PHLA. Poly(HEMA) and poly(LysMA) were intended to provide, respectively, resistance to non-specific protein adsorption and the ability to lyse incipient clots. The heparin-like moiety, sulfonated ß-cyclodextrin was immobilized on the PU-PHLA via host-guest interactions with the poly(AdaMA). This component is expected to inhibit coagulation and smooth muscle cell proliferation and to promote endothelialization. The resulting materials were shown to have multifunctionalities including fibrinolytic activity, anticoagulant activity and the ability to promote endothelial cell adhesion and inhibit smooth muscle cell adhesion. This work provides a new strategy for the development of multifunctional, endothelial-mimicking, biomaterials for blood contacting applications.

A hemocompatible polyurethane surface having dual fibrinolytic and nitric oxide generating functions.

Thrombus formation remains a serious problem in developing blood compatible materials. Despite continuous, intensive efforts over many years to prepare surfaces that prevent clotting, such surfaces have not been achieved; indeed it seems that surface-induced clotting is inevitable. An alternative approach is to accept that clotting will occur and to design surfaces so that small, nascent clots will be lysed before they can cause harm. The generation of plasmin, as in the fibrinolytic system, may be adopted for this purpose. The vascular endothelium (the inner surface of intact blood vessels) releases nitric oxide (NO) on a continuous basis. NO protects against platelet activation and aggregation, and also has an anti-proliferative effect on smooth muscle cells (SMCs). Based on these two important functions of the vascular system, the approach of constructing a fibrinolytic surface that generates NO is developed in the present work. Poly(oligo(ethylene glycol) methyl ether methacrylate-co-6-amino-2-(2-methacylamido)-hexanoic acid) (poly(OEGMA-co-LysMA)) was attached to a vinyl-functionalized polyurethane (PU) surface by graft polymerization giving a surface (PU-POL) with protein-resistant properties (via poly(OEGMA)) and clot lysing properties (via poly(LysMA)). Selenocystamine, which catalyzes S-nitrosothiol decomposition to generate NO in the vasculature, was then immobilized on the PU-POL surface via covalent attachment. A dual functioning surface with fibrinolytic activity (lysis of nascent clots) and NO releasing ability (inhibition of platelet adhesion and SMC adhesion as well as proliferation) was thereby constructed.