Synthesis, characterization, and blood compatibility of polyamidoamines copolymers
Introduction
Blood-contacting biomaterials and artificial organs such as artificial blood vessels, pumps, and artificial heart require improved blood compatibility for clinical uses. At present, the most serious performance problem is surface-induced thrombus formation immediately after implantation of materials in the living system. A substantial part of the current research on biomaterials is focused on the design and preparation of polymers with perfect or near-perfect blood compatibility. It is the surface of a biomaterial, which first comes into contact with the living body when the biomaterial is placed in the body or fresh blood. Therefore, the initial response of the living body to the biomaterial depends on its surface properties [1], [2], [3]. Many strategies have been adopted for the synthesis of blood-compatible polymers. One of the methods involves the introduction of highly hydrophobic groups to a hydrophilic polymer [4], [5], [6]. Other approaches include use of biological anti-coagulants such as heparin, prostaglandin, urokinase and, chemical modifications [7], [8], [9]. Heparin, a heterodisperse mucopolysaccharide, has been extensively used in prophylaxis and treatment of thrombotic disorders [10]. Heparin-immobilized polymers have been shown to improve blood compatibility because of the bioactivity of grafted heparin. To avoid excess heparin administration, many researchers have attached heparin to polymer surface by ionic or covalent bonding [11], [12], [13]. It has been shown that polyamidoamines (PAAs) possess the ability to selectively adsorb heparin from plasma or blood giving stable complexes without any adverse effect on plasma proteins and blood cells [14], [15]. PAAs prepared by nucleophilic addition of diamines to acryloyl piperazine (Pip) had shown little significance in biomedical fields due to their poor mechanical properties [16]. Tanzi et al. [17] synthesized a poly-ether-urea-urethane by copolymerization of 4,4′-diphenylmethanediisocanate (MDI), propanediamine, and poly-oxytetramethylene glycol. Similarly differentially terminated poly(amidoamine) (PAA) oligomers were grafted on the surface of poly(ether urethane amide)s (PEUAm) with fumaric or maleic acid moieties by Michael type addition of amino-groups to activated double bonds in the PEUAm backbone and the materials displayed enhanced heparin adsorption ability [18]. Their heparin adsorption ability, blood compatibility, and cytotoxicity have been evaluated. PAAs were also obtained in a linear form by stepwise polyaddition of primary monoamines or bis(secondary amines), to bis-acrylamides, and endowed with heparin-complexing ability [19]. Azzuoli et al. [20] grafted PAA chains onto the surface of polyurethane. Heparin formed complexes onto the surface with PAA-g-polyurethane, which improved the blood compatibility of polyurethane. Barbucci et al. [21] coated different commercial materials such as polyurethane, polyvinyl chloride, glass, etc., with well-characterized biomaterials PUPA (a copolymer of polyurethane and PAA) to improve hemocompatibility. In vitro results of heparin-coated PUPA devices offered significantly improved blood compatibility [22]. These PUPA surfaces were capable of adsorbing large amounts of heparin due to the basic nitrogens of poly(amidoamine), which once protonated, electrostatically interact with the negative charges carried by the heparin molecules. Yang et al. [23] had grafted dimethyl-aminoethylmethacrylate (DMAEMA) onto styrene-butadiene-styrene (SBS) tri-block copolymer membrane by UV-radiation induced graft copolymerization. The amount of adsorption of albumin and fibrinogen decreased in the graft amount and the heparin content. The blood compatible characteristics of the polyamides had been improved by introducing amidoamine groups in the polymer backbone [24]. Heparinization of the block copolymers had shown a significant improvement in blood compatibility as evident from thrombus formation and hemolysis study. It appears, therefore, that method of heparinization may be one of the best-adopted techniques to prepare the anti-thrombogenic polymer.
In the present study, attempts have been made to synthesize two different PAAs derived from polyaddition reaction of Pip and cyclohexylamine (CHA) separately with N,N′-methylene bis-acrylamide (MBA). Subsequent copolymerization of these PAAs with methylmethacrylate (MMA) along with their physico-chemical characterization and thrombogenicity of the polymers are reported.
Section snippets
Reagents
MBA (E. Merck, Germany), Pip, and CHA (SRL, India) were used as such. MMA (CDH, India) was made inhibitor free using 2% NaOH solution and by subsequent distillation. Glutaraldehyde (25% solution) of Reidel-de-Haen, Germany was used. Sodium salt of heparin (1000 IU) was obtained from Gland Pharma (India). All other chemicals of used in the study such as, acetone, toluene, sodium hydroxide, methanol, benzoyl peroxide, etc., were of laboratory grade.
Instrumentations
The FTIR spectra were recorded in Perkin-Elmer
Solubility and intrinsic viscosity
The freshly prepared polymer (5 mg) was suspended over 10 ml of the chosen solvent and the solubility was checked after 2 h. It was found that (Table 1) PAAs were soluble in water almost immediately at room temperature where as the corresponding copolymers were insoluble in water. Toluene served as an ideal solvent for dissolving both the PAAs and copolymers along with homopolymer PMMA. In acetone, and chloroform, however, a typical behaviour was noticed. In acetone the PAAs were insoluble,
Conclusion
Two new polyamidoamines consisting of piperazine-N,N′-methylene bis-acrylamide (Pip-MBA) and cyclohexylamine-N,N′-methylene bis-acrylamide (CHA-MBA) having heparin binding capability were synthesized and subsequently copolymerized with methyl methacrylate (MMA) under suitable reaction conditions to yield two copolymers (Pip-MBA-MMA and CHA-MBA-MMA). The solubility behaviour of the synthesized polymers showed marked difference in their properties with respect to their compositions. Observation
Acknowledgements
Financial support from Life Science Research Board (LSRB), DRDO, (letter number DALS/48222/LSRB-23/EPB/RD-81/2001) was gratefully acknowledged. One of the authors (RKD) is thankful to the authorities of JITM, Parlakhemundi, Orissa, for giving him necessary permission to carry out the work.
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