Stem cell therapy: MRI guidance and monitoring

Abstract

With the recent advances in magnetic resonance (MR) labeling of cellular therapeutics, it is natural that interventional MRI techniques for targeting would be developed. This review provides an overview of the current methods of stem cell labeling and the challenges that are created with respect to interventional MRI administration. In particular, stem cell therapies will require specialized, MR-compatible devices as well as integration of graphical user interfaces with pulse sequences designed for interactive, real-time delivery in many organs. Specific applications that are being developed will be reviewed as well as strategies for future translation to the clinical realm.

Figure 1

Fast spin echo image of one million iron oxide-labeled mesenchymal stem cells, which appear hypointense in an agarose phantom (left). Using a positive contrast imaging technique (25) the iron oxide-labeled stem cells appear hyperintense in a typical dipole pattern (right).

Figure 2

Long-axis MR images (left) of the left ventricle with magnified view (right) showing hypointense lesions (arrow) caused by iron oxide-labeled mesenchymal stem cells injected under x-ray fluoroscopy acquired within 24 hours (top) and 1 week (bottom) of injection. Expansion of the hypointense region at 1 week is indicative of local migration of the stem cells. Adapted from Kraitchman et al (38), which contains expanded contiguous image data and histological validation.

Figure 3

Long-axis MR images (4.0 msec repetition time, 2.0 msec echo time, 70° flip angle, 240 mm² field of view, 160 × 160 matrix, 8 mm section thickness, 2 frames per second) acquired in water bath containing nitinol catheter and different active coil elements. a: Only the external surface coil elements were active. b: Only the catheter coil was active. c: Only the catheter tip microcoil was active. d: Both surface coil elements and active catheter coil are contributing to the image. Reprinted with permission from Saeed et al (65).

Figure 4

Screen capture of the Siemens prototype Interactive Front End (IFE) graphical interface that enables real-time scan plane manipulation and serial acquisition of up to three imaging planes. The image is reconstructed with the active injection catheter colored green for enhanced visibility. Representative pseudo long- and short-axis images are shown acquired in real-time in vivo in a canine reperfused myocardial infarction. Bookmark images (small images at bottom) facilitate rapid return to previous scan plane position using a simple drag-n-drop of the image plane into one of three image acquisition planes.

Figure 5

High-resolution, ECG-gated, breath-hold steady-state free precession short-axis images prior to contrast injection (left), and after transmyocardial gadolinium-based contrast injection with tissue vital dye (middle) under MR fluoroscopy. Postmortem digital image (right) demonstrates a high concordance of the spatial location and extent with in vivo MRI.

Figure 6

a: The distal tip of a custom, MR-compatible active injection catheter (66) that was used for injections of 10% gadolinium with a tissue vital dye. b: ECG-gated, breath-hold long-axis image prior to injection. c: Long-axis image after first gadolinium injection mixed with a blue dye. d: Long-axis image after second gadolinium injection with green dye. Unfortunately, injection sites can only be appreciated for a short period of time due to wash-out of the gadolinium contrast agent. e: Postmortem image demonstrating distinct injection sites. Adapted from Karmarkar et al (66).

Figure 7

Targeting of the iron oxide-labeled stem cell injections to the peri-infarction area was performed based on delayed contrast-enhanced short-axis MRI (left) in which hyperintense signal represents myocardial infarction (MI) in this acute, reperfused canine model. Short-axis, high-resolution fast gradient echo image (right) of the left ventricle demonstrating multiple hypointensities (arrows) from iron oxide-labeled mesenchymal stem cells that were injected under MR fluoroscopy. Adapted from Bulte and Kraitchman (17).

Figure 8

Still-frame captures of three-plane view from the Siemens interactive graphical interface demonstrating guiding an active catheter into the left ventricle from a carotid artery approach. Images were acquired with a nongated steady-state free precession pulse sequence. The needle of the injection catheter is colored yellow. In frame (f) the gain from the active catheter is reduced to enable better determination of the catheter position.

Figure 9

Top: A single pseudo-long axis-plane (left) and three-plane view (right) with an injection catheter shown in green prior to labeled stem cell injection. The catheter is steerable and flexible to enable access to many portions of the left ventricular endocardial surface. Bottom: During injection of iron oxide-labeled stem cells the active catheter gain is no longer colored to enhance detection of hypointensities in the myocardium to document stem cell injection success.

Figure 10

Three representative short-axis images at end-diastole (top row) and end-systole (bottom row) in a dog with a reperfused left anterior descending coronary artery myocardial infarction that received transmyocardially administered mesenchymal stem cells under MR fluoroscopy. Prior to injection at 72 hours postinfarction (images on left), tagged MRI with circumferential strain shown as a color overlay where less shortening is green and more shortening is blue demonstrates a mild functional defect in the anteroseptal wall (12 o’clock to 2 o’clock) that shows little functional improvement or slight worsening of function at 2 weeks posttransmyocardial mesenchymal stem cell delivery (images on right).