Studies On The Synthesis, Characterization And Biocompatibility Of Novel Copolymers Of Aliphatic Esters And Phosphates

Biodegradable and biocompatible aliphalic polyester is one of the synthetic polymer materials which is widely used in the research and application of biomedical materials and green polymer materials. However, because of its poor surface hydrophilicity and absence of natural molecule acting point, its application as biomaterials especially as drug delivery materials was limited.Polyphosphate is another new biodegradable material with a rapid development. Its main chain phosphate skeleton is similar to nucleic acid and phosphorus acid. The characteristics of degradation at physiological conditions, and vulnerablity and high variability of their structure make them to be modified easily. However, the fast degradation characteristic of polyphosphate restricted its application in drug release.In order to overcome these shortcomings and promote the application to public as better biomedical materials, this dissertation attempts to improve hydrophilicity and drug delivery performance of the aliphatic polyesters through copolymerization of aliphatic ester and phosphate ester, and introduction of the phosphorylcholine (PC) groups on both ends of poly(butylenes succinate). The results and conclusions are summarized as follows:(1) A series of copolymers containing aliphatic polyester and polyphosphoester segments in the repeat units were synthesized via condensation polymerization reaction with adipoyl chloride, ethyl dicholorophosphate and triethylene glycol as the beginning materials. The effects of reaction conditions on polymerization were studied and the structures of final polymers were characterized by ¹H NMR, FT-IR and MALDI-TOF MS. Dynamic contact angle was used to characterize the surface capability of the polymers. The controlled release character of the copolymers was studied by a fluorescence method using neutral red as a model drug. The experimental data displayed that strong hydrophilic polyphosphate has the fastest release rate, about 90% neutral red was released within 10 days; and strong hydrophobic aliphatic polyester has the slowest release rate, only 50% neutral red was released for 10 days. Hydropholicity and drug release rate of aliphalic polyester indeed can be regulated through the copolymerization of phosphate and aliphatic polyester. (2) A new biodegradable and biocompatible polymer, phosphorylcholine functionalized poly(butylene succinate) (PBS-PC) was synthesized via a four-step synthetic strategy. First, chloroethyl phosphoric acid dichloride was synthesized from POCl₃ and 2-chloroethanol. Second, hydroxyl functionalized poly(butylene succinate) (PBS) was synthesized through a condensation polymerization of dimethyl succinate and 1,4-butadiol. Then, the one-pot end capping reaction of the polymer hydroxyl was conducted and chloroethylphosphorate functionalized poly(butylene succinate) (PBS-Cl) was obtained. Finally, the target polymer bearing PC groups on PBS both ends (PBS-PC) was attained by quaterisation reaction. The results of NMR, FT-IR, GPC and XPS demonstrated a successful construction of the product of PBS-PC. As both the PBS-Cl and PBS-PC polymers contain phosphorus atom in their end groups, the P elemental composition is used to estimate the average number of the end functional groups of the polymer chains. The calculated numbers are 1.9 for both the PBS-Cl and PBS-PC polymers.(3) Thermal analysis of the synthesized PBS, PBS-Cl and PBS-PC were tested using differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA). Compared with the PBS, phosphatidate and PC groups on the PBS chain significantly retarded the crystallizability and the flexibility. The melting point and melting enthalpy of PBS-Cl and PBS-PC were lowed (PBS-PCPBS-Cl>PBS) was increased. Dynamic contact angle results showed that the introduction of PC groups increased the hydropholicity of the PBS (receding contact angle: 33.8°for PBS and 8.4°for PBS-PC). Dynamic contact angle, in vitro degradation, swelling behavior and drug release measurements revealed that the PBS-PC showed improved hydrophilicity, degradation, swelling and faster drug release rates by compared with PBS.(4) From hemolysis, cytotoxicity, platelet adhesion and protein adsorption (bovine serum albumin and bovine plasma fibrinogen) experiments, hemocompatibility and cell compatibility of polymers PBS, PBS-Cl and PBS-PC were studied systematically. Hemolysis experiment showed that hemolytic rate of the three polymers were all less than 5%, and compared to PBS and PBS-Cl, hemolytic rate of PBS-PC was the lowest. The results of cytotoxicity experiment using mouse L929 fibroblast cells as showed that whether the three polymers themselves or their extracts, no significant cytotoxicity was found. Compared with PBS and PBS-Cl, PBS-PC has a better cell affinity. The results of platelet adhesion test showed that the adhered platelets on the surface coated with PBS showed large sizes, which suggested the aggregation and agglomeration of platelet. This result indicated the activation of the platelets by the hydrophobic surface. On the other hand, the surface coated with PBS-PC almost no platelet adhesion, suggesting excellent anti-coagulation property. Protein adsorption test showed that the amounts of bovine serum albumin (BSA) and bovine plasma fibrinogen (BPF) absorbed on the PBS-PC coated surface were 0.1μg/cm² and 0.13μg/cm², respectively, which were 52% and 72% reduction compared with that on PBS surface.These results suggest that PBS-PC may have potential applications in biological environments as new carrier for controlled drug release, scaffold for tissue engineering or temporary coating for the endovascular implant systems.