On-demand degradable embolic microspheres for immediate restoration of blood flow during image-guided embolization procedures

Abstract

Degradable embolic agents that provide transient arterial occlusion during embolization procedures have been of interest for many years. Ideally, embolic agents are visible with standard imaging modalities and offer on-demand degradability, permitting physicians to achieve desired arterial occlusion tailored to patient and procedure indication. Subsequent arterial recanalization potentially enhances the overall safety and efficacy of embolization procedures. Here, we report on-demand degradable and MRI-visible microspheres for embolotherapy. Embolic microspheres composed of calcium alginate and USPIO nanoclusters were synthesized with an air spray atomization and coagulation reservoir equipped with a vacuum suction. An optimized distance between spray nozzle and reservoir allowed uniform size and narrow size distribution of microspheres. The fabricated alginate embolic microspheres crosslinked with Ca²⁺ demonstrated highly responsive on-demand degradation properties in vitro and in vivo. Finally, the feasibility of using the microspheres for clinical embolization and recanalization procedures was evaluated with interventional radiologists in rabbits. Digital subtraction angiography (DSA) guided embolization of hepatic arteries with these embolic microspheres was successfully performed and the occlusion of artery was confirmed with DSA images and contrast enhanced MRI. T2 MRI visibility of the microspheres allowed to monitor the distribution of intra-arterial (IA) infused embolic microspheres. Subsequent on-demand image-guided recanalization procedures were also successfully performed with rapid degradation of microspheres upon intra-arterial infusion of an ion chelating agent. These instant degradable embolic microspheres will permit effective on-demand embolization/recanalization procedures offering great promise to overcome limitations of currently available permanent and biodegradable embolic agents.

Keywords: Embolic agents; Embolization; Embolotherapy; Interventional radiology; On-demand degradable microspheres.

Fig. 1.

(a) Schematic illustration of air atomizing spray-coagulation set-up for fabricating Alg-USPIO microspheres, (b) A spray-pattern image taken with a planar red laser (650 nm). The prepared alginate solution was sprayed using a compressed air (20 psi)-assisted spray equipment. The spray pattern showed two divided regions of air-pressure-driven-atomization and turbulence. (c) Morphology of microspheres fabricated by the spray-coagulation in different distance of the nozzle-to-reservoir (white bar represents 50 μm). (d) A table for mean size and size distribution of fabricated microspheres in various condition.

Fig. 2.

(a) Size and size distribution of Alg-USPIO microspheres, (inset) An optical microscopic image of Alg-USPIO microspheres (scale bar: 50 μm). (B) A schematic of the principle of on-demand degradation with ion chelating EDTA agent. (c) In vitro on-demand degradation of Alg-USPIO microspheres dispersed in a blood serum. White bars represent 50 μm. (d) Degradation time of microspheres dispersed in blood serum or Milli-Q water from the addition of EDTA solution (EDTA concentration: 1, 5, 10 and 30 mM).

Fig. 3.

(a) Optical microscope images of (top and middle) In vitro on-demand degradation of embolized Alg-USPIO microspheres in a capillary and (bottom) collected solution after the on-demand degradation of Alg-USPIO microspheres (white bars: 30 μm), (b) In vivo embolization and on-demand degradation in subcutaneous micro-vessel of mice. (white bars: 1 mm).

Fig. 4.

(a) (top) Schematics of in vivo embolization and on-demand degradation in white rabbit liver model and (bottom) DSA images confirming the procedures of catheterization (red arrow indicates the point of embolic agent infusion), embolization (blue arrows indicate an occlusion of left and right hepatic artery due to embolic agent), and on-demand recanalization (red arrow shows the continuous occlusion of left hepatic artery, blue arrow shows recanalization of right hepatic artery had started immediately after treatment of EDTA, and white arrow indicates the point of EDTA treatment with arterial catheter) in rabbit model. (b) (top) Schematics of procedures and (bottom) Gd contrasted enhanced T1 weighted and 3D-rendered MR images at each procedure of catheterization, embolization and on-demand degradation. (c) (top) Schematics of procedures and (bottom) T2 weighted MR images showing occluded MRI visible Alg-USPIO microspheres at each procedure of catheterization, embolization and on-demand degradation.

Fig. 5.

(top) H&E and (bottom) Prussian blue stained tissue images (4×, 10× and 20× magnification). On-demand degradation group was treated with EDTA on-demand recanalization of hepatic artery embolized with Alg-USPIO microspheres. Control group was treated with IA infusion of PBS. (CV: central vein, PV: portal vein, HA: hepatic artery, and BD: bile duct).