Tracking Cell Transplants in Femoral Osteonecrosis with Magnetic Resonance Imaging: A Proof-of-Concept Study in Patients

Abstract

Purpose: Osteonecrosis is a devastating complication of high-dose corticosteroid therapy in patients with cancer. Core decompression for prevention of bone collapse has been recently combined with the delivery of autologous concentrated bone marrow aspirates. The purpose of our study was to develop an imaging test for the detection of transplanted bone marrow cells in osteonecrosis lesions.

Experimental design: In a prospective proof-of-concept clinical trial (NCT02893293), we performed serial MRI studies of nine hip joints of 7 patients with osteonecrosis before and after core decompression. Twenty-four to 48 hours prior to the surgery, we injected ferumoxytol nanoparticles intravenously to label cells in normal bone marrow with iron oxides. During the surgery, iron-labeled bone marrow cells were aspirated from the iliac crest, concentrated, and then injected into the decompression track. Following surgery, patients received follow-up MRI up to 6 months after bone marrow cell transplantation.

Results: Iron-labeled cells could be detected in the access canal by a dark (negative) signal on T2-weighted MR images. T2* relaxation times of iron-labeled cell transplants were significantly lower compared with unlabeled cell transplants of control patients who were not injected with ferumoxytol (P = 0.02). Clinical outcomes of patients who received ferumoxytol-labeled or unlabeled cell transplants were not significantly different (P = 1), suggesting that the added ferumoxytol administration did not negatively affect bone repair.

Conclusions: This immediately clinically applicable imaging test could become a powerful new tool to monitor the effect of therapeutic cells on bone repair outcomes after corticosteroid-induced osteonecrosis.

Conflict of interest statement

Conflict of Interest Statement: The authors declare no potential conflicts of interest.

©2018 American Association for Cancer Research.

Figures

Fig. 1:. Study Concept.

(A) 24–48 hours prior to a planned core decompression for ON treatment, patients received an intravenous injection of the FDA-approved iron supplement ferumoxytol. (B) Ferumoxytol is taken up by cells in normal bone marrow, leading to hypointense (dark) signal on MRI. (C) 24–48 hours after iron supplement administration, iron labeled bone marrow cells were harvested from the iliac crest during core decompression. (D) The osteonecrotic bone was decompressed by drilling a track to the ON through a minimally invasive procedure and (E) iron labeled bone marrow cells were injected through the decompression track.

Fig. 2:. Serial MR images of osteonecrosis before and after core decompression and transplantation of iron labeled bone marrow cells.

(A) T1-weighted, T2-weighted and x-ray images of the right femur shows an osteonecrosis (arrows) in the femoral epiphysis with typical fat-equivalent center and serpiginous borders. (B) 24 hours after intravenous injection of ferumoxytol, the normal bone marrow in the iliac crest shows hypointense (dark) enhancement (asterisks) on T2-weighted MR images. (C) One week after core decompression and injection of iron labeled bone marrow cells, a hypointense (dark) signal is noted in the decompression track (arrows), consistent with delivery of iron labeled cells. MRI follow-up at (D) 4 weeks and (E) 24 weeks after core decompression and transplantation of labeled cells shows decline in iron signal over time. The femoral epiphysis did not collapse during this 6 month follow up period.

Fig. 3:. Ferumoxytol labeled cell transplants can be detected in the decompression track after core decompression.

(A) Coronal T2-weighted MR image of the left femur of a patient, who was treated with core decompression and injection of iron labeled cells into the decompression track. Areas of hypointense (dark) signal (arrow) are noted in the decompression track, consistent with delivery of iron labeled cells (B) Superimposed color-coded signal intensities show areas of iron labeled cells (arrow) as displayed by blue color. (C) Coronal T2-weighted MR of the left femur of a patient, who was treated with core decompression and injection of unlabeled cells into the decompression track. Unlabeled cells are noted by an intermediate signal in the decompression track. (D) Superimposed color-coded signal intensities show medium ranged signal intensities (green/yellow) (E) Signal to Noise Ratios (SNR) and (F) T2* relaxation times during the first week after surgery for areas that showed iron signal compared to areas where iron labeled cell were not delivered and unlabeled controls show significantly lower SNR (P = 0.002, n = 18; P = 0.002, n = 10; respectively) and T2* relaxation times (P = 0.007, n = 9; P = 0.02, n = 6; respectively). (G) SNR and (H) T2* relaxation times at 4–7 weeks reveal no significant differences between the groups, suggesting interval iron metabolization. Data are means ± standard error of the mean. P values were determined by mixed effects model including a random effect term accounting for correlation among the measures within a same patient. (I) Time to progression of ON between labeled and unlabeled cell transplants are not significantly different (P = 0.8, n = 16). P value was determined by log rank test.