Magnetic resonance fluoroscopy allows targeted delivery of mesenchymal stem cells to infarct borders in Swine

Abstract

Background: The local environment of delivered mesenchymal stem cells (MSCs) may affect their ultimate phenotype. MR fluoroscopy has the potential to guide intramyocardial MSC injection to desirable targets, such as the border between infarcted and normal tissue. We tested the ability to (1) identify infarcts, (2) navigate injection catheters to preselected targets, (3) inject safely even into fresh infarcts, and (4) confirm injection success immediately.

Methods and results: A 1.5-T MRI scanner was customized for interventional use, with rapid imaging, independent color highlighting of catheter channels, multiple-slice 3D rendering, catheter-only viewing mode, and infarct-enhanced imaging. MRI receiver coils were incorporated into guiding catheters and injection needles. These devices were tested for heating and used for targeted MSC delivery. In infarcted pigs, myocardium was targeted by MR fluoroscopy. Infarct-enhanced imaging included both saturation preparation MRI after intravenous gadolinium and wall motion. Porcine MSCs were MRI-labeled with iron-fluorescent particles. Catheter navigation and multiple cell injections were performed entirely with MR fluoroscopy at 8 frames/s with 1.7x3.3x8-mm voxels. Infarct-enhanced MR fluoroscopy permitted excellent delineation of infarct borders. All injections were safely and successfully delivered to their preselected targets, including infarct borders. Iron-fluorescent particle-labeled MSCs were readily visible on delivery in vivo and post mortem.

Conclusions: Precise targeted delivery of potentially regenerative cellular treatments to recent myocardial infarction borders is feasible with an MR catheter delivery system. MR fluoroscopy permits visualization of catheter navigation, myocardial function, infarct borders, and labeled cells after injection.

Figure 1

Comparison of Gd-DTPA–enhanced infarct-imaging techniques. A, Conventional IR-GRE DHE. B, Real-time steady-state free precession. Infarcted tissue is visible but difficult to distinguish from LV cavity blood. C, Real-time steady-state free precession with a saturation prepulse (sat-RT-SSFP). DHE is visible by real-time methods without ECG gating or breath holding. Saturation prepulse improves real-time delineation of endo-cardial infarct border.

Figure 2

Catheter tracking using 3D multislice MR fluoroscopy: A, Thin slice of catheter (green) within LV. Distal end is outside of scan plane and therefore not visible. B, By switching to a catheter-only mode, entire catheter becomes visible, analogous to x-ray projection.

Figure 3

MR fluoroscopy injection sequence. A, Stiletto is engaged at apical septal border of anterior myocardial infarction. MRI signal from needle tip is red and that from guiding catheter green. Arrows indicate previous injections of iron-labeled stem cells, which show as dark signal voids. B, A 150-μL test injection of Gd-DTPA is indicated by arrowhead and shows as white. C, Saturation-preparation enhances appearance of test injectate compared with black myocardium and blood. D, Iron-labeled MSCs (1×10⁶) are injected into same spot, extinguishing local signal, and appear dark.

Figure 4

Precise targeting of infarct border of a small infarct. A, Conventional inversion recovery DHE showing small area of infarction (arrow). B, Real-time steady-state free precession image of second injection into infarct border. C, Postinjection high-resolution gated, breath-held steady-state free precession image clearly showing 2 border injections.

Figure 5

A, 3D postmortem MRI shows injections (arrowheads) along border of infarct (bright yellow). B, Fluorescent micrograph of an infarct border shows red IFPs within injected MSCs. C, Differential phase image of same section shows tissue fast dye in black (arrow). Overlaying fluorescent image identifies IFP-labeled MSCs. D, Desmin stain of same section shows intact myocardium in green. E, Neighboring section shows perinuclear IFPs surrounding blue DAPI-stained nuclei within MSCs.