Study On The Construction And Properties Of Fibrinolytic Material Surfaces

Surface induced thrombosis remains the major cause of failure of implanted blood contacting medical devices.Most surface modification strategies for preparing anti-thrombotic materials are focused on the‘inhibition of fibrin formation',however intensive research over several decades proved that thrombosis happening on the foreign material surface can not be avoided.Developing fibrinolytic surfaces is an effective strategy to solve this problem.Tissue plasminogen activator(t-PA)and plasminogen(Pig)are essential components of the fibrinolytic system.t-PA can convert Pig into plasmin,which can dissolve fibrin clot.In view of this,immobilizing these active proteins on the surfaces will endow materials with fibrinolytic activity.In this thesis,more strategies for developing fibrinolytic surface were developed.Firstly,a surface with dual-affinity for t-PA and Pig was designed for in situ plasmin generation and clot lysis.The polyurethane surface was modified with a copolymer of poly(1-adamantan-1-ylmethylmethacrylate-co-2-hydroxyethyl methacrylate)(PHA),followed by attachment,in sequence,of the ARMAPE peptide and ?-CD-(Lys)7.The resulting surfaces were shown to resist nonspecific protein adsorption and have high affinity for t-PA and Pig.When the surface pre-loaded with t-PA and exposed to plasma,Pig was adsorbed selectively on the surface and activated to plasmin by t-PA is situ,thus endowing the surface with fibrinolytic property.The incorporation of dual affinity ligands for plasmin generation,illustrated in the present work,may show a promising method for developing materials with in situ generated specific bioactivity.Directly modifying surface with bioactive agents may cause side effects by reason of over express of activity.Considering this,a novel concept of a material which had thrombus-responsive fibrinolytic activity had been developed.The concept was tested using a t-PA-loaded polyacrylamide hydrogel crosslinked by peptide which can be cleaved by thrombin.The hydrogel was shown to only degrade and release t-PA in serum with thrombin(generated in thrombus formation).The rates of hydrogel degradation and t-PA release could be adjusted by changing the crosslinking degree of the hydrogel.t-PA release was found to be dependent on the concentration of thrombin and could be controlled in an“on-off”manner corresponding to the presence and absence,respectively,of thrombin.What is more,the hydrogel had the ability to lyse fibrin specifically in the presence of thrombin,indicating thrombosis-responsive fibrinolytic properties.The t-PA loaded hydrogel described above has potential for use as a coating on the surface of blood contacting devices.More generally speaking,the concept of thrombus-responsive fibrinolytic activity on blood contacting surfaces provides a design platform that should have wide applicability for developing anti-thrombogenic biomaterials.In order to obtain more effective anti-thrombotic materials,a surface coating with anti-coagulation property and fibrinolytic activity was developed.Poly lysine/heparin composite nanoparticle(PHs)were prepared by electrostatic interaction,we also got t-PA nanocapsules(t-PA NCs)by forming a thrombin-responsive degradable hydrogel on the surface of t-PA PHs and t-PA NCs were immobilized on the surface covered by polydopamine.The surface modified with two nanoparticles can not only repel the adsorption of nonspecific protein,but also inhibit the coagulation pathway due to the presence of heparin,beyond this,when the coagulation cannot be stoped on account of the limited amount of heparin,the t-PA NCs'shell would degrade and initiate the fibrinolytic process,so that nascent clot will be dissolved.