An organic chemistry approach to the surface modification of biomedical devices to limit bacterial adhesion and blood coagulation

摘要

Introduction: A wide range of biomedical devices have to be implanted in the body and put in contact with blood. Most of the time, they are made of polymers such as polydimethylsiloxane or polyurethane having a hydrophobic surface. Two major problems are associated with the implantation of this kind of devices in the bloodstream: infection due to the adhesion of bacteria to the surface of the device and the formation of a biofilm; blood coagulation when blood proteins adsorb on the surface, as a starting point to the blood coagulation cascade that can lead to the adhesion of platelets and the formation of a blood clot in catheters for example. To avoid these complications, various strategies have been used: adsorption of anticoagulant polymers of the surface, addition of a surface modifying molecule to the polymer blend or chemical modification of the surface by different ways. However, on the market today there is no strategy that allows to improve hemocompatibility and to reduce bacterial adhesion in the same time with polyurethane implants by covalent binding of molecules or polymers at the surface. Our group previously proved that covalent grafting of methylcellulose onto silicone implants allowed a significant reduction of bacterial adhesion and blood coagulation in vitro and in vivo. We are interested in finding a strategy that would allow us to modify polyurethane surfaces in a single step, using soft reaction conditions, to lead to similar antiadhesive properties. Materials and Method: To better approach the chemical reactivity of polyurethane surfaces, model urethane molecules were synthesized and a screening of organic chemistry reactions was performed to modify these urethanes. Successful reaction conditions were scaled up to modify polyurethane device surfaces in order to graft bioactive molecules or polymers that would confer the desired properties to the surface. After modification, the modified surfaces were tested and analyzed ensure the efficiency of the modification. Surface analysis techniques (contact angle, ATR-FTIR, XPS, TOF-SIMS) were used to characterize the modified surface. Biological assays such as bacterial adhesion, cell adhesion, blood protein adsorption and blood coagulation were done to check the antiadhesive properties of modified surfaces. Results and Discussion: The successful reactions were used to modify polyurethane surfaces and confer them excellent antiadhesive properties. Hydrophilic surfaces were created as verified by contact angle measurements. Bacterial adhesion was reduced by 100-1000 fold depending on the polymer and reaction, and cell adhesion was significantly reduced. Blood protein adsorption was also significantly reduced. The modified surfaces were stable over time in air or aqueous media. Conclusion: A screening of reactions allow us to identify several reactions to graft polymers (PEG, polysaccharides…) and have efficient surface modification of polyurethane. The modified surfaces are hydrophilic and show excellent antiadhesive properties towards bacteria, blood proteins and cells. We have developped a very promising system to allow a one-step modification of polyurethane medical devices, using non toxic reagents and covalent binding of the grafted polymer.