In vitro assessment of new embolic liquids prepared from preformed polymers and water-miscible solvents for aneurysm treatment (original) (raw)
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Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2012
This study examines the in vitro characteristics of a crosslinking polymer system for cerebral aneurysm embolization. The polymeric material is composed of poly(propylene glycol)diacrylate (PPODA) and pentaerythritol tetrakis(3-mercaptopropionate) (QT), formulated with the liquid contrast agents Conray TM or Omnipaque TM 300. The PPODA-QT system was tested for delivery feasibility through mock delivery into a model aneurysm. Cytotoxicity was performed by exposing 3T3 cells to gel formulations, followed by a cell viability assay. Swelling was measured on samples submerged in 150 mM phosphate buffered saline at 37 or 50 C. The same samples underwent compression testing to assess degradation, characterized by reduction in Young's modulus over time. The PPODA-QT system was easily deliverable to mock aneurysms. Cytotoxicity results indicated that Conray-formulated gels are initially less toxic than Omnipaqueformulated gels, but show greater susceptibility to swelling and degradation over time. In general, these experiments represented more challenging conditions than would be present in vivo, and therefore, reported results are likely overestimations of in vivo outcomes. However, these results highlight potential issues with each PPODA-QT formulation. Given the desired outcome of neointimal tissue growth over the polymer material, initial cytotoxicity may be more important than longterm factors when choosing an optimal formulation for aneurysm embolization. V C 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 100B: 1298-1309.
We report the evaluation of dual-gelling poly (N-isopropylacrylamide)-based polymer systems as embolic agents for intracranial aneurysms. These hydrogels undergo gelation physically via temperature-responsiveness of poly (NIPAAm) and chemically through a Michael-addition reaction between thiol and vinyl functional groups on the copolymers. Cytotoxicity studies were performed for biocompatibility of the hydrogels. In vitro glass models were utilized to assess injectability and embolization using the gelling systems and an in vivo swine model was used as proof-of-concept for catheter delivery, injection, and occlusion properties of the hydrogels. Rheology creep tests were conducted for determination of viscoelastic behavior, and degradation of the hydrogels was also investigated. Live/dead and proliferation assays indicated good biocompatibility of the hydrogels. In vitro and in vivo assessment demonstrated that the hydrogels were easily delivered via catheters into the aneurysms. Slight recanalization was observed in vivo, with some adhesion of the gels to the balloon catheter seen in vitro. The materials show creep deformation occurring with time; however, the hydrogels did not degrade over the course of 1.5 year. With the possibility to engineer hydrogels bottom-up for particular applications, these studies show properties that need to be optimized for dual-gelling polymer systems to serve as liquid-to-solid embolic agents for aneurysm treatment. V C 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 00A: 000-000, 2013.
BACKGROUND AND PURPOSE: To evaluate the ready-to-use iodine-containing polyvinyl alcohol (I-PVA) dissolved in the low angiotoxic solvent N-methyl pyrrolidone (NMP) for embolization of porcine wide-necked aneurysms. METHODS: Fourteen broad-based carotid sidewall aneurysms were surgically constructed in 7 swine. I-PVA (40%) in NMP was injected under temporary balloon occlusion bridging the aneurysm neck. After 4 weeks, follow-up angiography, multisection CT angiography (MSCTA), and 3T MR imaging including MR angiography (MRA) sequences were performed. Afterward, harvested aneurysms were investigated histopathologically. RESULTS: The liquid embolic was well visible under fluoroscopy and displayed a favorable precipitation pattern, allowing for controlled polymer delivery. Ten aneurysms (71%) were initially completely occluded, whereas in 1 aneurysm, a minimal polymer leakage was observed. The other 4 aneurysms (29%) were almost completely occluded. One animal suffered a lethal rebleedi...
AJNR. American journal of neuroradiology, 2006
To evaluate the ready-to-use iodine-containing polyvinyl alcohol (I-PVA) dissolved in the low angiotoxic solvent N-methyl pyrrolidone (NMP) for embolization of porcine wide-necked aneurysms. Fourteen broad-based carotid sidewall aneurysms were surgically constructed in 7 swine. I-PVA (40%) in NMP was injected under temporary balloon occlusion bridging the aneurysm neck. After 4 weeks, follow-up angiography, multisection CT angiography (MSCTA), and 3T MR imaging including MR angiography (MRA) sequences were performed. Afterward, harvested aneurysms were investigated histopathologically. The liquid embolic was well visible under fluoroscopy and displayed a favorable precipitation pattern, allowing for controlled polymer delivery. Ten aneurysms (71%) were initially completely occluded, whereas in 1 aneurysm, a minimal polymer leakage was observed. The other 4 aneurysms (29%) were almost completely occluded. One animal suffered a lethal rebleeding from the anastomosis after uneventful e...
PDA journal of pharmaceutical science and technology / PDA
Generally, organic water-miscible solvents are used intravascularly (both intravenously and intra-arterially) for preparing two types of formulations, namely, pharmaceutical injections of poorly soluble drugs and precipitating liquid embolic polymeric materials for the minimally invasive treatment of aneurysms, arteriovenous malformations, or tumors, by arterial route. Although several of such solvents have been used in both drug delivery and interventional radiology, their safety profile is a concern. In particular, there is a lack of comparative investigations of their cardiovascular effects when injected intra-arterially. We selected 13 non-aqueous water-miscible solvents based on their capacity to solubilize drugs or embolic polymeric materials, and on their described use, at least diluted with water, in pharmaceutical formulations. Their in vivo hemodynamic toxicity in male adult sheep after infra-renal aorta catheterization has been estimated with respect to the arterial and v...
Embolization of cerebral aneurysms with a liquid embolus, EVAL mixture: Report of three cases
Acta Neurochirurgica, 1996
Embolization of three surgically difficult cerebral aneurysms was performed using our newly developed non-adhesive embolic material, EVAL mixture (ethylene vinyl alcohol copolymer). Conventional embolic materials such as detachable balloons or microcoils were not used because of a large or irregular aneurysmal neck. After temporary occlusion of the parent artery with a superselective balloon catheter, the EVAL mixture was slowly injected through a microcatheter placed in the aneurysm or parent artery. The locations of the aneurysms were anterior communicating artery, basilar artery-posterior cerebral artery and basilar artery-anterior inferior cerebellar artery (BA-AICA). One aneurysmal occlusion and 2 parent artery occlusions were performed. Patients had no persistent deficits. The patient with the BA-AICA aneurysm associated with an arteriovenous malformation died of rupture of the residual AVM due to haemodynamic change 2 weeks after embolization. In selected and limited cases, embolization of surgically difficult cerebral aneurysms using EVAL mixture was more effective and safer than embolization using conventional embolic materials such as balloons and microcoils.
Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2013
A liquid-to-solid gelling polymer system, such as the poly(ethylene glycol) diacrylate-pentaerythritol tetrakis (3mercaptopropionate) (PEGDA-QT) system, can fill cerebral aneurysms more completely than current embolization materials, reducing the likelihood of aneurysm recurrence. PEGDA-QT gels were formulated using PEGDA of different molecular weights (PEGDA 575 and PEGDA 700 ), and their characteristics were examined in vitro. Experiments examined gel time, mass change, crosslink integrity, cytotoxicity, and protein release capabilities. In general, PEGDA 575 -QT gels were more hydrophobic, requiring an initiating solution with a higher pH (pH 9.5) to achieve a gel time comparable to PEGDA 700 -QT gels, which used an initiating solution at pH 9.19. The mass change and crosslink integrity of gels were analyzed over time after gels were submerged in 150 mM phosphate buffered saline. After 380 days, PEGDA 575 -QT gels achieved a maximum mass increase of 72% due to water uptake, while PEGDA 700 -QT gels doubled their initial mass (100% increase) by 165 days. Compression tests showed that PEGDA 700 -QT gels hydrolyzed more quickly than PEGDA 575 -QT gels. Cytotoxicity assays showed that in general, PEGDA 575 -QT negatively affected cell growth, while PEGDA 700 -QT gels promoted cell viability. Sustained, controlled release of lysozyme, a 14.3 kDa protein, was achieved over an 8-week period when loaded into PEGDA 700 -QT gels, but PEGDA 575 -QT gels did not show sustained release. These studies show that although they are similar in composition, these PEGDA-QT gel formulations behave considerably differently. Although PEGDA 700 -QT gels swell more and degrade faster than PEGDA 575 -QT gels, their cytocompatibility and protein release characteristics may prove to be more beneficial for in vivo aneurysm treatment. V C 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 00B: 000-000, 2013.
Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2011
The use of liquid-to-solid curing materials for brain aneurysm embolization has become increasingly attractive, as liquid embolics can be delivered noninvasively and can potentially achieve a higher degree of aneurysm volume occlusion. This study was aimed at characterizing differences in the gelling process of a reverse emulsion, crosslinking polymer system formulated with different types of injectable contrast agents. The polymeric system consists of poly(propylene glycol) diacrylate (PPODA) and pentaerythritol tetrakis(3-mercaptopropionate) (QT). These monomers undergo Michael-type addition upon initiation by a basic, aqueous solution. Conray TM and Omnipaque TM 300, commercially available contrast agents, were pH-adjusted to basic conditions and used as initiating solutions with the PPODA-QT system. Material characteristics were identified through rheology and scanning electron microscopy (SEM). Results showed that Conray-and Omnipaque-formulated materials progress through the gelling process uniquely, evidenced by distinctly different viscosity profiles and droplet distributions. These results indicate that Conray is more miscible with the PPODA-QT organic phase. Greater solubility in the organic phase allows Conray-formulated gels to have faster and more widespread reaction initiation kinetics when Conray and Omnipaque have the same pH. Omnipaque-formulated gels require a higher pH for the material to solidify in a time frame comparable to Conray-formulated gels. This discrepancy arises because the majority of reaction initiation sites in Omnipaque-formulated gels occur at phase boundaries via hydroxide ion flux from emulsified droplets rather than from hydroxide ions that are solubilized and integrated within the PPODA-QT organic phase. V C 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 96B: 47-56, 2011.
AJNR. American journal of neuroradiology, 2003
Coiling of intracranial aneurysms is both safe and effective but may be followed by recurrences. The purpose of this study was to assess the feasibility of endovascular treatment of aneurysms with high-concentration ethylene-vinyl alcohol copolymer (HCEVOH), without the use of protection devices at the neck. Wide-necked bifurcation aneurysms with a high propensity for recurrences were constructed in 22 dogs. HCEVOH embolization was performed with a dedicated high-pressure microcatheter in 12 animals. Angiographic results at 3 and 12 weeks and pathologic results at 12 weeks were compared with those of a separate group of 10 animals treated with platinum coils. We used a qualitative scoring system to grade angiographic results, neointima formation, and recanalization at the neck. Intraaneurysmal HCEVOH injections could be performed without carotid emboli and without a protection device in 11 of 12 animals. Fragments detached upon traction of the microcatheters at the end of the proced...