Tracking Stem Cell Implants in Cartilage Defects of Minipigs by Using Ferumoxytol-enhanced MRI

Abstract

artilage defects due to trauma, degenerative arthritis, or inflammatory arthritis affect approximately one out of five adults and represent a major cause of pain and disability (1-3). Because cartilage defects do not heal spontaneously, interventions are needed to induce repair. Bone marrow-derived autologous mesenchymal stromal cells (MSCs) can differentiate into chondrocytes and have been implanted into cartilage defects to restore joint health (4). However, cartilage repair outcomes of matrix-associated stem cell implants (MASIs) in patients have been highly variable: While some investigators reported full-thickness hyaline cartilage regeneration (5,6), others reported a failure rate of up to 50% for MASIs (7,8). Limited cell transplant survival was identified as the most important obstacle for successful cartilage repair (9). An imaging test that could help predict MASI outcomes would greatly enhance our ability to develop more successful cell transplant procedures. MRI is the primary modality for cartilage imaging (10,11). However, MRI within the 1st few weeks after MASI cannot help distinguish between grafts that will and grafts that will not repair the underlying cartilage defect (9). To date, successful cartilage repair is diagnosed many months after MASI, on the basis of a reduction in cartilage defect size at morphologic MRI (10,11). Unfortunately, failed cartilage repair and scar formation are difficult to correct at that time. Timely detection of an impending graft failure could enable rescue interventions

Nanotechnology and Osteoarthritis. Part 1: Clinical landscape and opportunities for advanced diagnostics

“…Similarly, the SPION‐labeling process does not adversely affect the phenotype or viability of chondrocytes or the production of major cartilage matrix constituents in vitro or in vivo 46,53‐55 . Ferumoxytol‐labeled matrix‐associated stem cell implants (MASIs) show significant T2 shortening (22.2 ± 3.2 vs 27.9 ± 1.8 ms; P < .001) and no difference in cartilage repair outcomes compared with unlabeled control MASIs ( P > .05) in a porcine model, as described by Theruvath et al 56 2 weeks after implantation, ferumoxytol‐labeled apoptotic MASIs show a loss of iron signal and higher T2 relaxation times compared with ferumoxytol‐labeled viable MASIs (26.6 ± 4.9 vs 20.8 ± 5.3 ms; P = .001) 56 . Standard MRI shows incomplete cartilage defect repair of apoptotic MASIs at 24 weeks.…”

“…Standard MRI shows incomplete cartilage defect repair of apoptotic MASIs at 24 weeks. Signal loss at 2 weeks correlates with incomplete cartilage repair, diagnosed at histopathologic examination at 12 to 24 weeks 56 . Chen et al describe an ultrasmall superparamagnetic iron oxide (USPIO)‐labeled cellulose nanocrystal/silk fibroin‐blended hydrogel system for noninvasive visualization and semiquantitative analysis of hydrogel degradation and cartilage regeneration in vitro and in rabbit cartilage regeneration in vivo 57 .…”

Iron nanoparticle-labeled murine mesenchymal stromal cells in an osteoarthritic model persists and suggests anti-inflammatory mechanism of action

“…Typically, DMM treated mice are followed out to 8-16 weeks after DMM surgery when changes in cartilage degradation are observed [16]. These time points are too long for us to perform iron-based short-term cell tracking as ferumoxytol is a biodegradable nanoparticle that cannot be retained for such long durations [37]. might be to reduce synovial inflammation and fibrosis, and this was supported by our data, which showed an increase in inflammation-resolving macrophages in the synovium, and a decrease in proinflammatory cells, and decrease in fibrosis.…”

Ascorbic Acid and Iron Supplement Treatment Improves Stem Cell–Mediated Cartilage Regeneration in a Minipig Model

“…To obtain porcine MSCs, bone marrow was aspirated from the iliac crest using a Jamshidi needle (Covidien). 48 Bone marrow cells were aspirated into a 20-mL syringe, which was supplemented with heparin (1000 USP U/mL; App Pharmaceuticals). The cell aspirate was transferred into test tubes, centrifuged at 1500 rpm for 5 minutes, suspended in Dulbecco's modified Eagle medium (DMEM) containing 10% fetal bovine serum (FBS) and 1% penicillin and streptomycin (Life Technologies), and then cultured in 225-cm 2 flasks (Corning) in 5% CO 2 at 37°C.…”

“…After completion of the final MRI examination, at 12 weeks after surgery, the pigs were euthanized with intravenously administered potassium chloride (900 mg/kg) under anesthesia, and knee joints were explanted and assessed according to the macroscopic International Cartilage Repair Society (ICRS) score ranging from 0 (worst) to 12 (best) 50 as well as the macroscopic score of Wayne et al 53 48 Cartilage regeneration was assessed according to the Pineda score ranging from 0 (best) to 14 (worst) 41 and the quantification of stained collagen type II areas. Images were analyzed using the Immunohistochemistry Image Analysis Toolbox in ImageJ (National Institutes of Health) as described previously.…”