A Novel Inherently Radiopaque Bead for Transarterial Embolization to Treat Liver Cancer - A Pre-clinical Study

Abstract

Purpose: Embolotherapy using microshperes is currently performed with soluble contrast to aid in visualization. However, administered payload visibility dimishes soon after delivery due to soluble contrast washout, leaving the radiolucent bead's location unknown. The objective of our study was to characterize inherently radiopaque beads (RO Beads) in terms of physicomechanical properties, deliverability and imaging visibility in a rabbit VX2 liver tumor model.

Materials and methods: RO Beads, which are based on LC Bead® platform, were compared to LC Bead. Bead size (light microscopy), equilibrium water content (EWC), density, X-ray attenuation and iodine distribution (micro-CT), suspension (settling times), deliverability and in vitro penetration were investigated. Fifteen rabbits were embolized with either LC Bead or RO Beads + soluble contrast (iodixanol-320), or RO Beads+dextrose. Appearance was evaluated with fluoroscopy, X-ray single shot, cone-beam CT (CBCT).

Results: Both bead types had a similar size distribution. RO Beads had lower EWC (60-72%) and higher density (1.21-1.36 g/cc) with a homogeneous iodine distribution within the bead's interior. RO Beads suspension time was shorter than LC Bead, with durable suspension (>5 min) in 100% iodixanol. RO Beads ≤300 µm were deliverable through a 2.3-Fr microcatheter. Both bead types showed similar penetration. Soluble contrast could identify target and non-target embolization on fluoroscopy during administration. However, the imaging appearance vanished quickly for LC Bead as contrast washed-out. RO Beads+contrast significantly increased visibility on X-ray single shot compared to LC Bead+contrast in target and non-target arteries (P=0.0043). Similarly, RO beads demonstrated better visibility on CBCT in target arteries (P=0.0238) with a trend in non-target arteries (P=0.0519). RO Beads+dextrose were not sufficiently visible to monitor embolization using fluoroscopy.

Conclusion: RO Beads provide better conspicuity to determine target and non-target embolization compared to LC Bead which may improve intra-procedural monitoring and post-procedural evaluation of transarterial embolization.

Keywords: Embolization; Hepatocellular carcinoma; TACE; VX2; radiopaque beads.

Figure 1

Comparison of LC Bead and Radiopaque LC Bead (RO Bead) dye attachment. Acrylamido polyvinyl alcohol-co-acrylamido-2-methylpropane sulfonate hydrogel (PVA-AMPS) beads are reacted with Reactive Blue 4 (RB4) to make LC Bead visible (blue) to the user. RB4 is substituted with a triiodobenzyl moiety via a linker (L) for RO Beads which imparts a slight yellow color and importantly renders them visible on X-ray.

Figure 2

Optical micrographs of RO Beads. A) 40-90 µm, B) 70-150 µm, C) 100-300 µm and D) 300-500 µm. E) Relative frequency distribution of RO Beads size measured with an optical microscope (N = 200-214).

Figure 3

In vitro penetration assay for LC Bead and Radiopaque Bead. The bar graphs depict penetration potential according to bead size. The bottom of the bar is the maximum penetration of the bead and the top of the bar is the trailing edge of a bead population (0.5 mL aliquot of sedimented beads). The maximum penetration and the the trailing edge for each size range was measured and displayed as an average (N=3).

Figure 4

Micro-CT of homogeneous RO Beads phantoms. A) Single 2D projection, B) Slice through reconstructed data, and C) Column of individual beads (~160 µm diameter).

Figure 5

A) 2D X-ray images of RO Beads line phantoms. Standard fluoroscopy (top row) and X-ray single shot (bottom row) show a series of microfuge tubes with horizontal line phantoms mimicking blood vessels of various inner diameters. B) Multidetector computed tomography of RO Beads phantoms with a six factor serial dilution of RO Beads ranging from 12.5 to 0.39% sedimented bead volume (vol%).

Figure 6

LC Bead in iodinated soluble contrast medium (LC Bead+contrast), RO Beads in iodinated soluble contrast medium (RO Beads+contrast) and RO Beads in dextrose (RO Beads+dextrose) on real-time fluoroscopy during administration and X-ray single shot following delivery. Arrowheads indicate target artery opacification whereas arrows highlight reflux into non-target arteries. *Identifies the gallbladder.

Figure 7

High dose CBCT performed post-euthanasia after the delivery of 1.1 cc of RO Beads suspension (0.055 cc RO Beads sedimented volume) delivered in iodinated soluble contrast medium. A) Axial image: contrast retention in the tumor is observed (short arrows). Linear attenuation in the wall of the gallbladder (asterisk) and hepatic arteries (arrowheads) are evidenced. Non-target delivery is shown in a gastric artery in the wall of the stomach (long arrow). B) Multi-planar reconstruction demonstrated contrast retention in the tumor located in the left hepatic lobe (short arrows). Linear attenuation consistent with a tumor feeding and normal hepatic arteries is also shown (arrowheads). Contrast retention is observed in the wall of the gallbladder (black asterisk). Non-target delivery is shown in gastric arteries and the wall of the stomach (long arrow). C) 3D volume rendering image in coronal view demonstrating the hepatic arteries (arrowheads), non-target delivery (long arrow), the tumor located in the left hepatic lobe (short arrow) and hyperattenuation of the wall of the gallbladder (black asterisk).