Fatemeh Zehtabi

Chitosan-doxycycline hydrogel: An MMP inhibitor/sclerosing embolizing agent as a new approach to endoleak prevention and treatment after endovascular aneurysm repair

The success of endovascular repair of abdominal aortic aneurysms remains limited due to the development of endoleaks. Sac embolization has been proposed to manage endoleaks, but current embolizing materials are associated with frequent recurrence. An injectable agent that combines vascular occlusion and sclerosing properties has demonstrated promise for the treatment of endoleaks. Moreover, the inhibition of aneurysmal wall degradation via matrix metalloproteinases (MMPs) may further prevent aneurysm progression. Thus, an embolization agent that promotes occlusion, MMP inhibition and endothelial ablation was hypothesized to provide a multi-faceted approach for endoleak treatment. In this study, an injectable, occlusive chitosan (CH) hydrogel containing doxycycline (DOX)-a sclerosant and MMP inhibitor-was developed. Several CH-DOX hydrogel formulations were characterized for their mechanical and sclerosing properties, injectability, DOX release rate, and MMP inhibition. An optimized formulation was assessed for its short-term ability to occlude blood vessels in vivo. All formulations were injectable and gelled rapidly at body temperature. Only hydrogels prepared with 0.075M sodium bicarbonate and 0.08M phosphate buffer as the gelling agent presented sufficient mechanical properties to immediately impede physiological flow. DOX release from this gel was in a two-stage pattern: a burst release followed by a slow continuous release. Released DOX was bioactive and able to inhibit MMP-2 activity in human glioblastoma cells. Preliminary in vivo testing in pig renal arteries showed immediate and delayed embolization success of 96% and 86%, respectively. Altogether, CH-DOX hydrogels appear to be promising new multifunctional embolic agents for the treatment of endoleaks. STATEMENT OF SIGNIFICANCE An injectable embolizing chitosan hydrogel releasing doxycycline (DOX) was developed as the first multi-faceted approach for the occlusion of blood vessels. It combines occlusive properties with DOX sclerosing and MMP inhibition properties, respectively known to prevent recanalization process and to counteract the underlying pathophysiology of vessel wall degradation and aneurysm progression. After drug release, the biocompatible scaffold can be invaded by cells and slowly degrade. Local DOX delivery requires lower drug amount and decreases risks of side effects compared to systemic administration. This new gel could be used for the prevention or treatment of endoleaks after endovascular aneurysm repair, but also for the embolization of other blood vessels such as venous or vascular malformations.

An injectable chitosan/chondroitin sulfate hydrogel with tunable mechanical properties for cell therapy/tissue engineering

Chitosan (CH) hydrogels with remarkable mechanical properties and rapid gelation rate were recently synthesized by combining sodium hydrogen carbonate (SHC) with another weak base, such as beta-glycerophosphate (BGP). To improve their biological responses, in the present study, chondroitin sulfate (CS) was added to these CH hydrogels. Hydrogel characteristics in terms of pH and osmolarity, as well as rheological, mechanical, morphological and swelling properties, were studied in the absence and presence of CS. Effect of CS addition on cytocompatibility of hydrogels was also assessed by evaluating the viability and metabolic activity of encapsulated L929 fibroblasts. New CH hydrogels containing CS were thermosensitive and injectable with pH and osmolality close to physiological levels and enhanced swelling capacity. Encapsulated cells were able to maintain their viability and proliferative capacity up to 7 days and CS addition improved the viability of the cells, particularly in serum-free conditions. Addition of CS showed a reducing and dose-dependent effect on the mechanical strength of the hydrogels after complete gelation. This work provides evidence that CH-CS hydrogels prepared with a combination of SHC and BGP as a gelling agent have a promising potential to be used as thermosensitive, injectable and biocompatible matrices with tunable mechanical properties for cell therapy applications.

New Alcohol and Onyx Mixture for Embolization: Feasibility and Proof of Concept in Both In Vitro and In Vivo Models

IntroductionOnyx and ethanol are well-known embolic and sclerotic agents that are frequently used in embolization. These agents present advantages and disadvantages regarding visibility, injection control and penetration depth. Mixing both products might yield a new product with different characteristics. The aim of this study is to evaluate the injectability, radiopacity, and mechanical and occlusive properties of different mixtures of Onyx 18 and ethanol in vitro and in vivo (in a swine model).Materials and MethodsVarious Onyx 18 and ethanol formulations were prepared and tested in vitro for their injectability, solidification rate and shrinkage, cohesion and occlusive properties. In vivo tests were performed using 3 swine. Ease of injection, radiopacity, cohesiveness and penetration were analyzed using fluoroscopy and high-resolution CT.ResultsAll mixtures were easy to inject through a microcatheter with no resistance or blockage in vitro and in vivo. The 50%-ethanol mixture showed delayed copolymerization with fragmentation and proximal occlusion. The 75%-ethanol mixture showed poor radiopacity in vivo and was not tested in vitro. The 25%-ethanol mixture showed good occlusive properties and accepted penetration and radiopacity.ConclusionMixing Onyx and ethanol is feasible. The mixture of 25% of ethanol and 75% of Onyx 18 could be a new sclero-embolic agent. Further research is needed to study the chemical changes of the mixture, to confirm the significance of the added sclerotic effect and to find out the ideal mixture percentages.