Ahmed Fatimi

A new injectable radiopaque chitosan-based sclerosing embolizing hydrogel for endovascular therapies

Endovascular repair of abdominal aortic aneurysms with a stent graft is limited by the persistence or recurrence of endoleaks. These are believed to be related to the recanalization of the aneurismal sac by endothelialized neochannels, which could lead to late type I and II endoleaks. Embolization has been proposed to treat or prevent endoleaks, but presently commercialized embolizing materials have several drawbacks and do not fully prevent endoleak recurrence. A novel chitosan hydrogel that is injectable, radiopaque and contains sodium tetradecyl sulfate (STS), a well-known sclerosing agent, was developed in order to combine blood flow occlusion and endothelium ablation properties. chitosan/STS hydrogels were characterized and optimized using rheometry, scanning electron microscopy, swelling and ex vivo embolization assay. They were shown to exhibit rapid gelation and good mechanical properties, as well as sclerosing properties. Their potential for the embolization of aneurysms was subjected to preliminary in vivo evaluation in a bilateral iliac aneurysm model (three dogs) reproducing persistent endoleaks after endovascular aneurysm repair (EVAR). At 3 months no endoleak was detected in any of the three aneurysms treated with chitosan/STS hydrogels. In contrast, type I endoleaks were detected in two of the three aneurysms treated with chitosan hydrogels. Generally, chitosan/STS hydrogels have great potential as embolizing and sclerosing agents for EVAR and possibly other endovascular therapies.

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

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.

Embolization and Endothelial Ablation With Chitosan and Sodium Sotradecol Sulfate: Preliminary Results in an Animal Model

Purpose To investigate whether embolization with chitosan hydrogel (CH) with or without a sclerosant (sodium tetradecyl sulphate, STS) can induce chemical endothelial ablation and prevent endothelial recanalization in a rabbit model. Methods Chitosan radiopaque thermogels were prepared using chitosan, β-glycerophosphate, iopamidol, and different STS concentrations. Each auricular artery of 14 New Zealand White rabbits was cannulated and injected with 0.6 mL of chitosan (CH0; n = 14) on one side and either saline (n = 3), chitosan and 1% STS (CH1; n = 6), or chitosan and 3% STS (CH3; n = 6) in the contralateral side. Immediately after embolization and at 1, 7, 14, and 30 days, auricular artery patency and percentage of recanalization were assessed by visual inspection; microcirculation was evaluated using laser Doppler imaging (LDI). The rabbits were sacrificed at 30 days to assess endothelial ablation and inflammatory response by histological analyses. Results All arteries were catheterized and embolized with success. All saline-injected arteries rapidly recovered normal flow. The length of embolization was greater with CH3 than CH1 or CH0, regardless of the time observed (p<0.001). No difference in recanalization length was found among the gels (p = 0.07). Destruction of arterial wall was frequently observed independent of embolizing agent. Foreign body reaction was more frequent with CH3 as compared with CH1 and CH0 (p = 0.0070 and 0.0058, respectively). After 30 days, hypervascularization was observed on LDI only with CH0; it was attributed to intra- or perivascular neovessels and inflammatory response on pathological analysis. The vascular modifications appeared to be more homogenous across the length of embolization with CH3 than the other formulations. Conclusion The viscosity obtained with chitosan and 3% STS permits better control during injection and longer vascular occlusion. These findings, combined with the intravascular neovascularization observed with CH0, led us to prefer the combination with STS.

Rheological studies of an injectable radiopaque hydrogel for embolization of abdominal aortic aneurysms

Several embolizing agents have been tested for minimally invasive treatment of intracranial aneurysms, and more recently to prevent or treat persistent blood flow (endoleaks) in abdominal aortic aneurysms. However, frequent recurrence of endoleaks was seen in most studies, suggesting that current embolization agents are not satisfying yet. Here we report rheological studies of a radiopaque chitosan hydrogel as an embolizing agent. The aim is to provide an agent that would be visible during x-ray based guided interventions. In this study, a commercial contrast agent (iopamidol) was associated to chitosan at different concentrations and its influence on the rheological behavior of chitosan thermogel was evaluated. The resulting hydrogels have a homogenous coherent structure. The addition of iopamidol leaded to an initially more viscous solution. To have a good visibility of hydrogel via x-ray, an optimum iopamidol concentration of 20% v/v was chosen. The addition of 20% v/v iopamidol increased the gelation time. The use of a high βGP concentration constitutes a solution to overcome the slowing down of gelation by 20% v/v iopamidol. Formulations containing around 16-20% βGP provides viscous solutions which rapidly gel and could be promising injectable radiopaque hydrogels for embolization.