Synthesis of biomimetic segmented polyurethanes as antifouling biomaterials I. Francolini ⇑ , F. Crisante, A. Martinelli, L. D’Ilario, A. Piozzi Department of Chemistry, ‘‘Sapienza’’ University of Rome, Piazzale Aldo Moro, 5, 00185 Rome, Italy article info Article history: Received 24 June 2011 Received in revised form 22 September 2011 Accepted 17 October 2011 Available online 22 October 2011 Keywords: Polyurethanes Heparin-like polymers Antifouling surfaces Biomimetic polymers Bacterial adhesion abstract Controlling the non-specific adsorption of proteins, cells and bacteria onto biomaterial surfaces is of cru- cial importance for the development of medical devices with specific levels of performance. Among the strategies pursued to control the interactions between material surfaces and biological tissues, the immo- bilization of non-fouling polymers on biomaterial surfaces as well as the synthesis of the so-called bio- mimetic polymers are considered promising approaches to elicit specific cellular responses. In this study, in order to obtain materials able to prevent infectious and thrombotic complications related to the use of blood-contacting medical devices, heparin-mimetic segmented polyurethanes were synthe- sized and fully characterized. Specifically, sulfate or sulfamate groups, known to be responsible for the biological activity of heparin, were introduced into the side chain of a carboxylated polyurethane. Due to the introduction of these groups, the obtained polymers possessed a higher hard/soft phase segrega- tion (lower glass transition temperatures) and a greater hydrophilicity than the pristine polymer. In addi- tion, the synthesized polymers were able to significantly delay the activated partial thromboplastin time, this increased hemocompatibility being related both to polymer hydrophilicity and to the presence of the –SO 3 H groups. This last feature was also responsible for the ability of these biomimetic polymers to pre- vent the adhesion of a strain of Staphylococcus epidermidis. Ó 2011 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. 1. Introduction Segmented polyurethanes are an important class of thermo- plastic elastomers, being widely employed in the medical field for the manufacture of medical devices such as vascular grafts, catheters, artificial blood vessels and heart valves. Their successful employment in clinics is mainly related to their good blood com- patibility and suitable mechanical properties arising from their structure of hard and soft segments [1]. One of the main drawbacks related with the use of blood-con- tacting medical devices is the high risk of infections and thrombo- sis associated with their implantation [2,3], these two complications being closely interrelated. In fact, upon exposure to the biological environment, plasma proteins, including fibrin, albumin and fibrinogen, adsorb on the device’s surface, allowing the adhesion and activation of platelets and leukocytes. This pro- cess, known as biofouling, is usually the first stage of a cascade of biological events which leads to blood clot formation and pro- motes bacterial adhesion and biofilm formation on device surfaces. The resulting infectious and thrombotic complications can impair the function of the device and lead to implant failure and life- threatening consequences, as in the case of vascular grafts. A common approach pursued to reduce biofouling is the immo- bilization of non-fouling polymers on biomaterial surfaces. This strategy is particularly interesting since it avoids the use of drugs (either by systemic administration or by local release from medi- cated devices) that, when administered over long periods of time, may be associated with undesired side effects. On the basis of the empirical criteria recently proposed by Ostu- ni and colleagues [4], non-fouling polymers should be hydrophilic, electrically neutral and possess hydrogen-bond acceptors. Accord- ingly, several polymer classes have been explored [5], including polyacrylates [6], polyzwitterions [7,8] and poly(ethylene glycol) (PEG) derivates [9,10]. Of these, PEG, which has the ability to im- part protein resistance, believed to be related to both hydration and steric effects [11], is the most widely studied non-fouling poly- mer. It has been grafted onto the surface of a series of materials, including glass [12], gold [13], poly(ethylene terephthalate) [14] and polyurethanes [15] with variable degrees of success, depend- ing on the PEG’s molecular weight, degree of branching and surface packing density. Although PEG possesses unique properties of non- toxicity and biocompatibility, a number of limitations have been associated with PEG grafting, including stability (autoxidation) and poor functionality [16]. Therefore, research in this field is still focused on the development of a more efficacious approach to ob- tain surfaces resistant to fouling by proteins, cells and bacteria. In this regard, the synthesis of biomimetic polymers [17–20], i.e. materials able to mime the biological environment, has lately 1742-7061/$ - see front matter Ó 2011 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.actbio.2011.10.024 ⇑ Corresponding author. Fax: +39 06 49913162. E-mail address: iolanda.francolini@uniroma1.it (I. Francolini). Acta Biomaterialia 8 (2012) 549–558 Contents lists available at SciVerse ScienceDirect Acta Biomaterialia journal homepage: www.elsevier.com/locate/actabiomat