Gelling process differences in reverse emulsion, in situ gelling polymeric materials for intracranial aneurysm embolization, formulated with injectable contrast agents.

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™ and Omnipaque™ 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.

Stimulation of in vivo angiogenesis using dual growth factor-loaded crosslinked glycosaminoglycan hydrogels.

Crosslinked, chemically modified hyaluronan (HA) hydrogels pre-loaded with two cytokine growth factors, vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1), were employed to elicit new microvessel growth in vivo, in both the presence and absence of heparin (Hp) in the gels. HA hydrogel film samples were surgically implanted in the ear pinnae of mice, and the ears were harvested at 7 or 14 days post-implantation. Analysis of neovascularization showed that each of the treatment groups receiving an implant, except for HA/Hp at day 14, demonstrated significantly more microvessel density than control ears undergoing surgery but receiving no implant (p<0.015). Treatment groups receiving either Ang-1 alone, or aqueous co-delivery of both Ang-1 and VEGF, were statistically unchanged with time. In contrast, film delivery of both growth factors produced continuing increases in vascularization from day 7 to day 14 in the absence of Hp, but decreases in its presence. However, presentation of both VEGF and Ang-1 in crosslinked HA gels containing Hp generated intact microvessel beds with well-defined borders. The HA hydrogels containing Ang-1+VEGF produced the greatest angiogenic response of any treatment group tested at day 14 (NI=7.44 in the absence of Hp and 4.67 in its presence, where NI is a neovascularization index). Even in the presence of Hp, this had 29% greater vessel density than the next largest treatment group receiving HA/Hp+VEGF (NI=3.61, p=0.04). New therapeutic approaches for numerous pathologies could be notably enhanced by the localized, sustained angiogenic response produced by release of both VEGF and Ang-1 from crosslinked HA films.