About 43 million individuals in the US currently suffer from disabilities due to arthritis. Cartilage defects are the major source of pain in the affected joints. Current treatments, whilst alleviating some of the clinical symptoms, prove insufficient to cure the underlying irreversible cartilage loss. Stem cells represent a unique source for restoration of cartilage defects. However, a major challenge with various approaches of stem cell and chondrocyte transplants is death of the transplanted cells with clearance by the immune system. The overall goal of this project is to develop a non-invasive and clinically applicable MR imaging technique, which provides an early diagnosis of complications of the engraftment process of matrix associated stem cell implants (MASI). The hypothesis is that viable and apoptotic MASI in arthritic joints demonstrate distinct signal characteristics on MR images, when combined with cell-specific MR contrast agents. In our current funding period, we have established labeling techniques for stem cell transplants with iron oxide nanoparticles and gadolinium chelates, and we have defined distinct signal characteristics of labeled viable and apoptotic MASI. During the new funding period, we will continue to use this approach to identify and develop strong candidate contrast agents for clinical translation. We plan to apply for an IND for clinical translation of the most promising approach by the end of this new funding period. In our pursuit of clinically applicable imaging approaches, we will first evaluate stem cell loss and/or apoptosis early after MASI via direct labeling of transplanted stem cells with the FDA-approved iron oxide nanoparticle ferumoxytol (Feraheme). In a second step, we will evaluate a novel caspase-sensitive MR contrast agent regarding its sensitivity to detect stem cell apoptosis in MASI with an arthrographic imaging approach. In a third step, we will identify failed MASI indirectly, via MR detection of the migration of iron oxide labeled bone marrow macrophages into MASI. Complementary optical imaging studies as well as confocal microscopy, immunohistochemistry and spectrometry studies will be performed to elucidate biological and physicochemical changes of the investigated cell transplants that lead to the observed MR signal characteristics. Results should be immediately helpful in the preclinical assessment of new stem cell based therapies for arthritis treatment, in the design of related clinical trials for hMSC therapy of arthritis, and ultimately, in the assessment of those hMSC therapy regimens in clinical practice. By exploiting novel, clinically applicable cell tracking techniques as a new too to monitor stem cell engraftment outcomes non-invasively in vivo, we anticipate significantly improving and accelerating the development of successful therapies for cartilage regeneration in patients, and ultimately, alleviating long term disabilities and related costs to our society. Sinc we address a generalized novel concept for imaging stem cell engraftment, results might not only impact patients with MASI but also patients with a variety of other (stem) cell transplants.

Public Health Relevance

The development of a non-invasive imaging technique for differentiation between viable and non-viable donor stem cells is crucial for monitoring of virtually any stem cell based therapy. A better understanding of the signal behavior of contrast agent labeled viable and apoptotic hMSC on MR images could help to investigate the mechanisms that control stem cell death and lead the way to a more effective use of hMSC-based therapies for arthritis. Results should be immediately helpful in preclinical assessments of hMSC-based therapies of arthritis and other joint pathologies, in the design of related clinical trials, and later, in the assessment of those stem cell based therapies in clinical practice.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Lester, Gayle E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Medicine
United States
Zip Code
Theruvath, Ashok Joseph; Sukerkar, Preeti Arun; Bao, Shanshan et al. (2018) Bone marrow oedema predicts bone collapse in paediatric and adolescent leukaemia patients with corticosteroid-induced osteonecrosis. Eur Radiol 28:410-417
Li, Kai; Chan, Carmel T; Nejadnik, Hossein et al. (2018) Ferumoxytol-based Dual-modality Imaging Probe for Detection of Stem Cell Transplant Rejection. Nanotheranostics 2:306-319
Chapelin, Fanny; Khurana, Aman; Moneeb, Mohammad et al. (2018) Tumor Formation of Adult Stem Cell Transplants in Rodent Arthritic Joints. Mol Imaging Biol :
Nejadnik, Hossein; Taghavi-Garmestani, Seyed-Meghdad; Madsen, Steven J et al. (2018) The Protein Corona around Nanoparticles Facilitates Stem Cell Labeling for Clinical MR Imaging. Radiology 286:938-947
Bulte, Jeff W M; Daldrup-Link, Heike E (2018) Clinical Tracking of Cell Transfer and Cell Transplantation: Trials and Tribulations. Radiology 289:604-615
Theruvath, Ashok J; Nejadnik, Hossein; Muehe, Anne M et al. (2018) Tracking Cell Transplants in Femoral Osteonecrosis with Magnetic Resonance Imaging: A Proof-of-Concept Study in Patients. Clin Cancer Res 24:6223-6229
Nejadnik, Hossein; Pandit, Prachi; Lenkov, Olga et al. (2018) Ferumoxytol Can Be Used for Quantitative Magnetic Particle Imaging of Transplanted Stem Cells. Mol Imaging Biol :
Daldrup-Link, Heike E; Chan, Carmel; Lenkov, Olga et al. (2017) Detection of Stem Cell Transplant Rejection with Ferumoxytol MR Imaging: Correlation of MR Imaging Findings with Those at Intravital Microscopy. Radiology 284:495-507
Daldrup-Link, Heike E (2017) Ten Things You Might Not Know about Iron Oxide Nanoparticles. Radiology 284:616-629
Li, Kai; Nejadnik, Hossein; Daldrup-Link, Heike E (2017) Next-generation superparamagnetic iron oxide nanoparticles for cancer theranostics. Drug Discov Today 22:1421-1429

Showing the most recent 10 out of 34 publications