| Recently, coronary artery stent implantation techniques are widely applied to the treatment of cardiovascular disease at home and abroad. However, some problems such as cardiovascular restenosis are crying out for solution. For this reason, a bioabsorbable drug-loaded coating which can be applied on the surface of blood vessel stents was designed in this work. The coating includes biodegradable poly (hydroxybutyrate-co-hydroxyhexanoate) (PHBHHx) as drug-loaded material and extract (ferulic acid) from Chinese angelica as drug. First, blood compatibilities and degradation properties of PHBHHx with different molecular weights were studied by in vitro test methods. Second, PHBHHx was surface-modified by a NaOH treatment, and the influence of the surface modification and its aging effect on the biocompatibility of PHBHHx were studied. Furthermore, the in vitro degradation property and the drug release property of the drug-loaded PHBHHx films were studied in this work. The function of the ferulic acid and the NaOH treatment on the endothelialization and inhibition of the blood vessel smooth muscle cell (VMSCs) proliferation was also discussed. The results are summarized as follows:The blood compatibility of PHBHHx with different molecular weights was evaluated in comparison with poly (L-lactic acid) (PLLA) by a haemolysis assay, plasma recalcification time (PRT), plasma prothrombin time (PT), kinetic clotting time and in vitro platelet adhesion test. The results showed that the blood compatibility of PHBHHx decreased with the increasing of molecular weight of PHBHHx. All PHBHHx films exhibited better blood compatibility than PLLA.It was thought that the cell adhesion and proliferation of PHBHHx were both worse than those of PLLA, due to the bad surface hydrophilic property of PHBHHx. The hydrophilic property of PHBHHx was effectively improved by a NaOH treatment, and thus the anticoagulation property, the cell adhesion and proliferation of the PHBHHx after the NaOH treatment also had a significant improvement.Further research found that the NaOH treatment exhibited an aging effect, which was caused by the partial reduction of polar groups on the sample surface. The main influence factors on the aging effect included the crystallinity of PHBHHx, the storage environment and the storage temperature. The aging effect speed could be effectively decreased by increasing the surface crystallinity of the samples, decreasing the storage temperature and laying the samples at 4℃in a hydrophilic environment under the normal biomaterials storage conditions. The good anticoagulation property and cell compatibility of PHBHHx after the NaOH treatment could be maintained by the above methods.By comparing macro-morphologies, micro-morphologies and in vitro static degradation speeds of the different drug-loaded PHBHHx films, it was confirmed that the appropriate weight ratios of ferulic acid to PHBHHx in the drug-loaded coating beyond the scope of our study were 5% and 10%. In vitro drug release properties of PHHBHx (5%) and PHBHHx (10%) films were studied and the result showed that the drug release from the drug-loaded PHBHHx films exhibited two stages: burst release and stabilization release. Primary mechanism of the drug release in the burst release stage was drug diffusion while the drug release in the stabilization release stage had a close relevancy and regularity to the degradation behaviors of the drug-loaded films.The results of the orthogonal test showed that the surface pretreatment of a magnesium alloy plays the most important role on the bonding strength between the drug-loaded coating and the magnesium alloy, closely followed by the drug charge and the preparation temperature. The preparation process which could lead to the highest bonding strength was that the magnesium alloy was surface pretreated by H3PO4 solution, the weight ratio of ferulic acid and PHBHHx was 5% and the preparation temperature was 40℃, corresponding to a bonding strength of 4.08±0.45MPa.In vitro biocompatibility test results showed that the ferulic acid release of the drug-loaded films had an obviously inhibition on the platelet aggregation and thrombosis and an effective improvement on the antihemolytic property and the anti-intrinsic and extrinsic coagulation properties of the drug-loaded films. Moreover, the human umbilical vein endothelial cells (HUVECs) adhesion and proliferation on the drug-loaded films could be significantly promoted and the VMSCs excessive proliferation could be effectively inhibited by the ferulic acid release.It was found that the NaOH treatment could improve the hydrophilic property of the drug-loaded films, further improve the HUVECs adhesion and proliferation properties, and accelerate the endothelialization process. On the other hand, NaOH treatment could sharply reduce the content of ferulic acid on the sample surface due to the etching action of NaOH, and then weakened the inhibition on VMSCs excessive proliferation on the drug-loaded films. In general, NaOH treatment was expected to control the cardiovascular restenosis by speeding up the endothelialization. |
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