Engineering a Reverse Thermo-Responsive, Cross-Linkable, Biodegradable Liquid Embolic Agent for Brain Aneurysm Treatment

Cerebral aneurysms are balloon-like dilations in intracranial arteries that can rupture, leading to fatal hemorrhagic stroke. The majority of current aneurysm treatments involve the implantation of catheter-based endovascular coils and meshes, but they result in unfavorable primary outcomes in at least 20% to 30% of cases [1]. This project aims to develop an injectable, controllably cross-linkable, durable, and multi-functional liquid embolic agent (LEA) using F88-DMA polymer that allows for the body’s natural mechanisms to heal the aneurysm with personalized biodegradation.<br/>As temperature increases and reaches physiological temperatures, F88-DMA micelles group together and entangle, resulting in mechanically strong physical gelation. Chemical crosslinkers ammonium persulfate (APS) and tetramethylenediamine (TEMED) enhance the long-term stability of the hydrogel, while iohexol acts as a contrast agent.<br/>In order to develop a pluronic-based polymer system that is deliverable in vivo, cold, radiopaque F88-DMA must be injectable through a microcatheter. Gelation must occur at the optimal time and temperature so as not to solidify prematurely or remain liquid within the aneurysm. Various concentrations of F88-DMA and TEMED were tested in vitro to determine the optimal concentration for injectability. Rheology results displayed that a higher concentration of F88-DMA lowers gelation temperature, and this correlation was further confirmed with differential scanning calorimetry for all three concentrations of F88-DMA (27%, 30%, and 33%). Additionally, higher concentrations of TEMED were found to increase the maximum shear modulus and decrease the crosslinking time of F88-DMA gel. To simulate interventional treatment, the LEA was injected into a brain aneurysm model, suggesting 29% F88-DMA to be the most injectable concentration that, when crosslinked, would remain in the aneurysm for prolonged periods of time.<br/>Upon gelation and crosslinking, hydrogels swell in situ due to thermodynamic forces, posing a significant risk for compression or rupture. F88-DMA hydrogel swelling was demonstrated to be dependent on polymer concentration (p = 0.019695), and the addition of iohexol significantly decreased swelling over the course of 3 days. Furthermore, hydrogels submerged in flowing saline exhibited less swelling than those submerged in static saline (p = 0.0001), an improved durability that originates from the entangled properties of the micelles.<br/>The durable embolic agent must also allow for vascular remodeling and endothelialization in a controlled manner. Thus, cell adhesion and porosity are vital. Imagery of fibrinogen-soaked gel suggests that natural levels of fibrinogen make the cross-linked F88-DMA cell adhesive enough, providing no need to incorporate cell adhesive materials. Sodium phosphate heptahydrate was effectively employed to control pre-determined porosity that initiates the wound healing process.<br/>After the aneurysm has healed, the pluronic implant must be controllably biodegradable. The biodegradability of the LEA is a function of the patient-specific wound healing process such that the blood vessel returns completely to its original healthy state. Naturally occurring enzymatic F88-DMA degradation is currently being investigated with lactide.<br/>Future studies will involve injecting this gel into rabbit models to examine its effects in vivo and determine rates of endothelization post-injection.<br/><br/>[1] Taschner CA, Chapot R, Costalat V, Machi P, Courtheoux P, Barreau X, et al. Second-Generation Hydrogel Coils for the Endovascular Treatment of Intracranial Aneurysms: A Randomized Controlled Trial. Stroke. 2018;49(3):667-74.