Experimental Study Of The National Eval Embolic Mixture

Objective ethylene vinyl alcohol copolymer (EVAL) was synthesized and nature test, biological detection and embolization in vitro by using it were performed to investigate its feasibility as a new embolic material. Rete mirabile (RMB) embolization by using EVAL in swine was performed to investigate technical feasibility, controllability and histopathological changes of EVAL for the treatment of cerebral arteriovenous malformations (AVM). Methods and materials 1.Laboratory StudyUnder4～5MPa,the free radical copolymerization happened in tertiary butyl accohol, ethylene and vinyl acetate and ethylene-vinylacetate copolymer formed.Then EVAL formed by adding methanol and strong base. We make EVAL solve in DMSO and put into tantalum pewder.High temperature sterilization was carried out in 30 minutes under 120°C.We undertook the transport mock-up test and embolism mock-up in vitro.The sample procducts has been test in Jinan medical instrument quality control and monitoring center for all nature detection. 2. Animal ExperimentSix healthy domestic pigs were used in this study. The animals were 3 to 4 months old, weighed 25 to 30 kg, and were mixed sex. According to the time interval of follow-up the animals were divided into three groups: acute term(same day of injection, 1 week after embolization), subacute term(4 weeks after embolization) and chronic term(8 weeks, 12 weeks, 24weeks after embolization),acute term included two animals,subacute term included one animal,chronic term included three animals. Each pig was premedicated with intramuscular lmg atropine and general anesthesia was maintained with ketamine and midazolam by intravenous administration during the procedure. A 5F vascular sheath was placed into the right common femoral artery using the Seldinger technique. A 5F guiding catheter was used to select the common carotid artery, through which a mti ultraflow HPC microcatheter was placed coaxially for superselective catheterization of the ascending pharyhgeal artery. The tip of the microcatheter was placed distal to the pharyngeal branch of ascending pharyngeal artery and selective angiography was performed. The national EVAL embolic mixture was aspirated into a 1-cc syringe and injected through the microcatheter. In order to prevent the mixture precipitation in the microcatheter, the mocrocatheter was flushed with dimethyl sulfoxide(DMSO) before injection of the national EVAL embolic mixture. Follow-up angiographywas performed for observation of revascularization. The animals were killed and the RMB and the brain were took out immediately for histological examination and the alterations of RMB and surrounding tissue were observed. Results 1. Laboratory StudyThe liquate index number of EVAL is 4 ～ 15g/10min.It can suit the command.When DMSO touch with water,it can diffuse immedicately and EVAL can separate.The time of sediment suit the medical command. We undertook the viscosity and particle content tests.The results appeared it can meet the command.The transport test appeared tantalum is suitable;but except Ultra Flow HPC micro catheter,the other micro catheter were corroded differently.The embolism test appeared the sample can embolism the AVM modle successfully.The copolymer has not been found in the microcatheter. The biology detection of the working samples demonstrated that there was no bacteria growth, the endotoxin level was less than 20EU/mL, the rate of haematolysis is 3.2%, there was no acute general toxicity with grade I cytotoxicity, and no intrademally irritating reaction, the rate of allergy was 0%,and implantation in vivo for 4, 12, and 26 weeks showed that the extent of reaction was consistent with the rule of GB/T16175, there was no inherent toxicity and the heavy metal content was less than 1.0μg/g, the change of pH was less than 1.5. All nature detection was consistent with the standard reguested. 2. Animal ExperimentEmbolization was performed in 7 RMB of 6 swine, the total dosages of the national EVAL were 1.3ml (0.19ml in average).After embolisms,all the animals survived without the abnormal states of sence and movement.The effects of embolisms were surprised. We draw the microcatheter easily except one catheter was packed for over reflux of the national EVAL.The tantlum as contrast-media was clearly seen under fluoroscopy.All the ascending pharyngeal artery or RMB of embolisms were not seen.The no embolisms of the ascending pharyngeal artery or RMB were seen by ramus anastomoticusthe (RA) and arteria anastomotica (AA) from internal maxillary arteries and RA or AA were larger than before.In macroscopy all the brains were normal except the black material was seen on the left cerebral peduncle in one pig and it is normal in histology.The different embolisms were seen in RMB,which diffused from caudal to rostral.The RMB of embolisms were harder than the.control sides and easily dissected.Histologic observation:In acute term,there were black embolisms and thrombus in RMB.There were many neutrophilic granulocytes in around the embolic mixtures and in the vessel walls.The intima, the elastic layer, the muscular layer and adventitia were not destroyed.Many red cells, eosinophilic granulocytes and neutrophilic granulocytes infiltrated around vessels.The left cerebral peduncle (there were black things in macroscopy)was normal except few inflammatory cells infiltrating.In subacute term,there were black embolisms and granulation tissues in the vessels There were mang inflammatory cells around the embolisms.The intima, the elastic layer, the muscular layer and adventitia were destroyed.There were histomonocytes, foreign body giant cells, histiocytes and gramulation tissues around the vessels.In chronic term,there were still many inflammatory cells in vessels and around vessels.It included histomonocytes, foreign body giant cells , histiocytes and lymphocytes.The embolisms stayed in the vessels.The vessel walls turned thin and were destroyed.There were mang granulation tissues and fibrous tissues in the vessels and around the vessels. Conclusion1 .The national EVAL has better biocompatibility and non-toxicity without general and inherent toxicity.2.The national EVAL is non-adhesive and could ebolize AVM model in vitro effectively.3.RMB embolization by using EVAL is technically feasible and controllable, embolic effective and stable with minor inflammation and EVAL may regarded as a new embolic material for clinical test.4.EVAL has great potential to be a non-adhesive embolic agent for endovascular treatment of cerebral AVMs and rich blood supply tumors.