Injectable, Dual-Cross-Linked, Dynamic Hydrogel for Tissue Separation and Thermal Shielding During Percutaneous Cryoablation

Image-guided percutaneous cryoablation is a minimally-invasive technique increasingly utilized in treatment of primary and metastatic tumors. However, close apposition of healthy and tumoral tissue often constrains the treatment zone and can lead to collateral organ injury. The present study aims to develop a hydrogel with which targeted percutaneous dissection may be performed to facilitate ablative therapy.

Materials and Methods:

A hydrogel was created by crosslinking alginate, calcium ions, and polyethylene glycol conjugated with boronic acid (Al-PB/Ca²⁺ gel). Stability of the gel and maintenance of structural integrity were assessed in vitro utilizing serum-containing cell culture media. Mechanical properties and viscosity of the hydrogel were studied using rheometric analysis at temperatures experienced during cryoablation. Insulation was assessed during freeze-thaw cycles (10 minutes at -80^°C, 5 minutes at 37°C repeated twice) within a gel matrix using temperature meters spaced at 5 mm intervals from the cryoablation probe. Cytotoxicity was examined through direct and indirect contact tests using human fibroblasts. Cytokine TNF-α release from mouse macrophages was measured to determine inflammatory effects of the gel. Following intraperitoneal instillation of the hydrogel in mice (n = 3), properties including tissue displacement, migration, and absorption were explored using serial ultrasound and MRI.

Results:

The Al-PB/Ca²⁺ gel hydrogel exhibited favorable shear-thinning behavior upon injection as well as self-healing properties upon repeated mechanical manipulation. Additionally, the gel demonstrated insulative properties during repeat freeze-thaw cycles, reaching a temperature nadir of -1.1^°C at a 15 mm distance from the cryoprobe. Viability of human fibroblasts was similar when cultured with and without the hydrogel for three days (100 vs. 92%, p = 0.65). Also, TNF-α secretion from macrophages in the presence of the gel (123.8 ± 99.4 pg/ml) was not significantly different than a no treatment control (47.5 ± 15.6 pg/ml, p = 0.98). Gel injection into the mouse peritoneum achieved successful bowel displacement with maintenance of tissue separation at six hours. Half of the gel remained at 24 hours, with nearly all the gel (95%) resorbed by 72 hours.

Conclusion:

This novel hydrogel demonstrates promising biocompatibility and physical properties for achieving tissue separation and thermal shielding during ablation. Forthcoming swine studies using CT-guided cryoablation will further elucidate in vivo efficacy and pave the way for human trials.