Determining the Relationship between Delivery Parameters and Ablation Distribution for Novel Gel Ethanol Percutaneous Therapy in Ex Vivo Swine Liver

Introduction: Ethanol ablation is a chemical ablation method that has the potential for global treatment of some cancers, especially superficial solid tumors accessible to injections since it can be performed by minimally trained personnel in the absence of electricity and/or surgical infrastructure. However, although inexpensive, ethanol is not widely used for tumor ablation as it tends to cause off-target leakage, resulting in irregularly shaped injectate distributions that typically do not span the entire tumor. Our group has developed a simple method for tumor ablation by mixing ethyl cellulose (EC), an inexpensive, natural polymer and derivative of cellulose, with ethanol before injection. EC increases ethanol viscosity and leverages the endogenous polarity difference between ethanol and water to induce a phase change from liquid to fibrous gel (gelation) upon injection into tissue. In situ gelation sequesters cytotoxic ethanol in the target region reducing off-target leakage. We have previously shown that EC-ethanol (ECE) exhibits decreased localized adverse events and increased overall survival compared to ethanol in syngeneic and spontaneous tumor models. For ECE ablation to be translated to a clinical setting a full understanding of the multivariate influence of injection parameters on the resultant ablation volume and shape is necessary. We therefore evaluated the formulation of ECE (viz. ethanol concentration) and key injection parameters in relation to the resulting force and distribution volume, retention and shape for clinically relevant tumor sizes as is typical for ablative therapies.

Materials and

Methods: Experiments were conducted to investigate how infusion volume (0.5 mL to 2.5 mL), ECE concentration (6% or 12%), needle gauge (22 G or 27 G), and infusion rate (10 mL/h ) impacted the force of infusion into air using a load cell. These parameters, with the addition of manual infusion, were investigated to elucidate their influence on depot volume, retention, and shape (aspect ratio), measured using CT imaging, in an ex vivo swine liver model. A 20% ethanol concentration was used as a cutoff value for segmentation. The depot volume (distribution volume of the injectate excluding spread into nearby collapsed vasculature), percent of infusion volume retained in the depot, and the aspect ratio were calculated from these segmentations.

Results, Conclusions, and Discussions: The force required for injection increased significantly for 12% compared to 6% ECE and for 27 G compared to 22 G needles. Force variability increased when a higher ECE concentration or a smaller needle diameter was used. As infusion volume increased, 12% ECE achieved superior depot volume compared to 6% ECE. For all infusion volumes, 12% ECE achieved superior retention compared to 6% ECE. Needle gauge and infusion rate had little influence on the observed depot volume or retention; however, the smaller needle diameter resulted in higher variability in depot shape for 12% ECE. Further, 12% ECE had a stronger positive correlation with depot volume and infusion volume than did 6% ECE, but they produced similar results at smaller volumes.
Our studies yield significant insights into the clinical translatability of ECE. Increasing ECE concentration improves retention but variability in distribution shape is seen when paired with smaller needle diameters. While needle gauge and infusion rate do not have a significant influence on the depot volume or retention of the ECE, the selection of smaller needle diameters and faster infusion rates will limit manual injections and could make them impossible due to the high forces required for injection. Both these parameters need to be balanced with lesion size in mind to maximize ethanol retention in the tumor. This study can also serve as the basis for the future creation of a predictive computational model that uses tumor biophysical properties as inputs to determine optimal injection parameters (infusion volume, infusion rate, and needle gauge). This would not only improve the overall injection optimization process, but also objectively account for the interacting roles of the many formulation and injection characteristics that govern injection outcomes.

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