No abstract

Thermosensitive semiinterpenetrating polymer networks (semi-IPNs) composed of cross-linked poly(JV-isopropylacrylamide) (NiPAAm) and linear poly(ether(urethane-urea) (Biomer) were obtained via UV-initiated solution polymerization. The semi-IPNs exhibited negative thermosensitivity, i.e., lower swelling levels with increasing temperature. The incorporation of a relatively small content of Biomer (up to 10 wt %) strongly influenced the mechanical properties, equilibrium swelling, and deswelling kinetics of synthesized networks. The semi-IPNs exhibited greater mechanical strength compared to the cross-linked poly(NiPAAm). Equilibrium swelling levels of the semi-IPNs at low temperatures were markedly decreased due to hydrophobic contribution of Biomer and higher apparent effective cross-linking densities of these networks. The gel collapse point, related to the lower critical solution temperature of poly(NiPAAm), was not affected. The semi-IPNs showed much faster deswelling rates compared to the cross-linked poly(NiPAAm). It was hypothesized that the presence of Biomer prevented the formation of a skin-type layer which normally retards the deswelling process of cross-linked poly(NiPAAm). Loading and release of heparin, a model macromolecule, was studied as a function of temperature and Biomer content in semi-IPNs. The partition coefficients of heparin within the networks decreased with increasing temperature and Biomer content. Similarly, a linear relationship between partition coefficients and equilibrium swelling in loading solutions was found for all synthesized networks. Heparin release profiles correlated with deswelling kinetics of crosslinked poly(NiPAAm) and NiPAAm/Biomer semi-IPNs. Release profiles were in agreement with the proposed mechanism of solute release from swollen thermosensitive gels.

HEMA/styrene (HEMA/STY) block copolymers and poly(ethylene oxide) 4,000 M.W. (PEO4K) grafted Biomer (B-PEO4K) surfaces have been synthesized, characterized, and evaluated as blood-contacting materials. These surfaces have demonstrated improved blood compatibility, compared to Biomer, in in vitro and ex vivo experiments. Biomer vascular grafts (6 mm I.D. 7 cm in length) were fabricated by a dip coating process. The luminal surface was modified either with PEO grafting, HEMA/STY coating, or Biomer coating (control). These surface-modified grafts were implanted in the abdominal aortas of dogs and evaluated for graft patency and protein adsorption. Surface protein layer thickness was measured by transmission electron microscopy (TEM). B-PEO4K and Biomer showed thick multilayers of adsorbed proteins (1000-2000 A) after 3 weeks to 1 month implantation. In contrast, HEMA/STY only showed a monolayer protein thickness (less than 200 A), even after 3 months. Visualization of adsorbed plasma proteins (albumin, IgG, and fibrinogen) was performed with scanning electron microscopy (SEM)/TEM using an immunogold double antibody technique. The pattern of protein distribution showed high concentrations of fibrinogen and IgG, and less albumin adsorbed onto Biomer and B-PEO4K. In contrast, HEMA/STY showed a patchy protein distribution pattern with high concentrations of albumin and IgG, and relatively less fibrinogen. Adsorbed monolayer patterns showed improved compatibility over multilayered proteins. The Biomer and B-PEO4K grafts occluded within 1 month, while HEMA/STY grafts were patent for over 3 months. The thin and stable adsorbed protein layer on HEMA/STY surfaces may be associated with the microdomain structures of the surface, and will play an important role in long-term in vivo blood compatibility. This manuscript will evaluate the long-term in vivo performance of these polymers, analyze the extent of protein adsorption onto the surfaces, and correlate protein layer thickness to the thrombogenicity of the polymer surfaces.

Biomer/poly(N-isopropylacrylamide)/[poly(NiPAAm)] thermosensitive polymer blends were prepared and their application as heparin-releasing polymer coatings for the prevention of surface-induced thrombosis was examined. The advantage of using poly(NiPAAm)-based coatings as heparin-releasing polymers is based on the unique temperature-dependent swelling of these materials. At room temperature, i.e., below the lower critical solution temperature (LCST) of poly(NiPAAm), the Biomer/(poly(NiPAAm) coatings are highly swollen. The high swelling enables fast loading of hydrophilic macromolecules (e.g., heparin) into the coating by a solution sorption technique. At a body temperature, i.e., above the LCST of poly(NiPAAm) the coatings are in a deswollen state and the absorbed macromolecules may be slowly released from a dense coating via a diffusion controlled mechanism. Biomer/poly(NiPAAm) coatings were obtained by blending and coprecipitation of the two linear polymers, Biomer and (poly(NiPAAm). The structure and water-swelling properties of the coatings were examined. Significant differences in water swelling at room temperature (RT) and 37°C were observed as a result of the thermosensitivity of poly(NiPAAm). The surface structure of the coatings in dry and swollen states at RT and 37°C was examined by scanning electron microscopy. Heparin was loaded into the coatings via a solution sorption at room temperature. Kinetic studies of heparin loading demonstrated that maximum loading was obtained within 1 h. The in vitro (37°C) release profiles were characterized by a rapid initial release due to the squeezing effect of the collapsing polymer network, followed by a slower release phase controlled by heparin diffusion through the dense coating. The short-term antithrombogenicity of intravenous polyurethane catheters coated with heparin-releasing Biomer/poly(NiPAAm) thermosensitive coating was evaluated in a canine animal model. The results show that the heparin release from Biomer/poly(NiPAAm)-coated surfaces resulted in a significant reduction of thrombus formation on test surfaces in contact with venous blood as compared to control surfaces.

A new synthetic approach for the preparation of segmented polyurethaneurea (SPUU)–PEO–Heparin graft copolymers (B–PEO–Hep) has been developed. The procedure involved the coupling of hexamethylene diisocyanate (HMDI) to soluble Biomer® (B) through an allophanate/biuret reaction. The free isocyanate (NCO) groups attached to Biomer® were then coupled to PEO terminal hydroxyl groups to form PEO grafted Biomer® (B–PEO). B–PEO free hydroxy groups were modified with HMDI to introduce terminal isocyanate groups. The NCO functionalized B–PEO was then coupled to heparin (Hep) functional groups (OH, NH2) producing B–PEO–Hep graft copolymer. Synthetic intermediates were confirmed by FTIR, NCO group determination, and toluidine blue heparin assay. Physical characterization techniques, such as contact angle measurements, water swelling, light scattering measurements, and DSC thermal analysis, detailed properties of the graft copolymer containing covalently bound heparin. This new heparinized copolymer can be applied as a coating on other existing blood contacting surfaces without changing bulk properties. The heparin bioactivity observed attests to the usefulness of this new procedure as a coating to improve the blood compatibility of blood‐contacting surfaces.