A new radiopaque embolizing agent for the treatment of endoleaks after endovascular repair: Influence of contrast agent on chitosan thermogel properties

Abstract

A new injectable radiopaque embolizing agent has been developed, based on chitosan thermogelling properties. Different commercial contrast agents (Isovue®, Visipaque®, and Conray®) were associated with chitosan-β-glycerophosphate. Their impact on gelation kinetic, mechanical properties, radiopacity, and cytotoxicity was tested to evaluate the best candidate and its feasibility for the treatment of endoleaks after endovascular aneurysm repair (EVAR). Addition of contrast agents did not prevent gelation at body temperature, but it significantly increased the viscosity of the solution before gelation, delayed gelation, and reduced the gelation rate. However, using chitosan with a high degree of deacetylation and 20 vol % contrast agent made it possible to obtain a gel with rapid gelation that was visible during X-ray based guided intervention. Hydrogels exhibit relatively low mechanical properties, which are only slightly modified by the addition of contrast agents. In vitro studies have demonstrated rapid release of contrast agents from hydrogels when immersed in a saline solution (>50% within 4 h). This is suitable for embolization, as radiopacity is required only to follow the embolization procedure, while long-term radiopacity would hamper further imaging and endoleak detection. Cytotoxicity and osmolality testing of extracts demonstrated some toxicity of products released by the gel during the first few hours, which is mainly related to their hypertonicity. After the first 24 h incubation, hydrogels released no more cytotoxic compounds, suggesting that the hydrogel rapidly becomes biocompatible. Altogether, this study suggests that the new radiopaque thermogels present interesting characteristics as embolizing agents for EVAR, although their mechanical properties require improvement.

Optimization and characterization of injectable chitosan‐iodixanol‐based hydrogels for the embolization of blood vessels

“…In contrast, here, chitosan with a 94% DDA provides much better gelation properties, with reduced gelation time and a much higher gelation rate. For example, CH/βGP12/VIS20 samples prepared here with a 94% DDA gelled immediately ( t = 0 min), and had a gelation rate of 60 Pa min −1 at 37°C, as compared to 24 min and 3 Pa min −1 for the same formulation prepared with an 83% DDA chitosan . This immediate gelation and relatively rapid increase in the G ′ values (indicative of elastic properties) could be obtained even with hydrogels containing the high content of contrast agent required to achieve good radiopacity (20–30%v/v VIS) .…”

“…This immediate gelation and relatively rapid increase in the G ′ values (indicative of elastic properties) could be obtained even with hydrogels containing the high content of contrast agent required to achieve good radiopacity (20–30%v/v VIS) . A comparison of the storage modulus after 1 week of gelation showed that the DDA did not however influence the final mechanical properties of the gel (about 1.5 kPa, in both cases) . The addition of VIS had only a small positive effect on the final mechanical properties of the gel.…”

“…Due to its rheological properties, biocompatibility, low toxicity, and structural similarity to natural glycosaminoglycans, chitosan hydrogels has found many biomedical applications, including tissue engineering and repair of cartilage, intervertebral disc and bone, as well as drug delivery systems . Recently, it was also shown to be a potential candidate for the embolization of blood vessels . Blood vessel embolization is a minimally invasive procedure that is increasingly being used for treatment of a wide range of conditions such as palliative cancer therapy (that is, trans‐arterial embolization (TAE), the treatment of vascular malformations, or to treat or prevent endoleaks following endovascular aneurysm repair (EVAR) .…”

Injectable thermosensitive chitosan hydrogels with controlled gelation kinetics and enhanced mechanical resistance

“…This is true, for example, for the embolization of blood vessels, where the gel must be resistant to blood flow (Coutu, Fatimi, Berrahmoune, Soulez, & Lerouge, 2013). Little data exists regarding the mechanical properties required to efficiently occlude blood vessels, but our work using in vitro embolization bench testing and animal experiments on other hydrogels suggests that good gel cohesion and a rapid increase of G to or above 1 kPa are minimum prerequisites for achieving these (Fatimi, Zehtabi, & Lerouge, 2015) (submitted).…”

Development of thermosensitive chitosan/glicerophospate injectablein situgelling solutions for potential application in intraoperative fluorescence imaging and local therapy of hepatocellular carcinoma: a preliminary study

“…The C/GP solution should form a gel quickly in order to provide good occlusion of blood flow [37]. The viscosity and compactness of the corresponding hydrogels that strictly depend on C and GP concentrations could be further critical parameters [36].…”