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NanoSTARS imaging for STEM cell therapy for arthritic joints

Periodic Reporting for period 2 - STARSTEM (NanoSTARS imaging for STEM cell therapy for arthritic joints)

Reporting period: 2019-07-01 to 2020-12-31

STARSTEM is developing a nanotechnology-enhanced optoacoustic imaging (OAI) approach, using a novel nanostar contrast medium, which will deliver unprecedented imaging depths and levels of sensitivity in identifying and tracking Mesenchymal Stem Cells (MSCs) and Extracellular Vesicles (EVs) and their healing function in osteoarthritis (OA) after administration into an affected joint.
Regenerative medicine, particularly stem cell therapy, has shown great potential in treating a wide range of illnesses, from arthritis to diabetes, cancer to transplant rejection. However, it is not yet clear how stem cells actually work inside the body. One of the major hurdles in stem cell mediated-therapy is the inability to sensitively monitor successful engraftment or activity of transplanted stem cells in real-time or over extended periods. There is limited knowledge about their biodistribution over time, engraftment, and mechanism of action.
Our nanotechnology-enabled imaging approach will help overcome these barriers to clinical translation, with a focus on OA. Arthritis is the most prevalent disease worldwide, with OA affecting around 10% of the global population and approximately 70 million patients in Europe. There is no effective cure for OA at present, and the majority of the treatments are symptomatic rather than restorative. Stem cell therapy provides a unique opportunity to help restore healthy function.
As such, STARSTEM will, for the first time, enable objective measurement of functional markers of healing, including vascularisation, oxygen saturation, and inflammation, over time and at significant depth. Understanding the hallmarks of the healing process will ultimately help patients to benefit from new cell therapies.
STARSTEM is a European project, with partners hailing from five countries; Ireland, Germany, England, Spain, and Italy. The project brings together leaders in the nanomaterials, regenerative medicine, osteoarthritis, and bio-imaging fields from across Europe.
STARSTEM will address major technology gaps to enable imaging of stem cells at clinically relevant depths. Our nanostar-enhanced multi-modal imaging approach will enable us to detect stem cell engraftment and tissue repair, and thus their activity and efficacy as a therapy.
STARSTEM began in January 2018 and will run for four years. Since project kick-off, we have made significant progress on cell production; isolation of EVs from MSCs; nanostar design and production; labelling of cell products; imaging technology development and software development; and the imaging of nanostar labelled cells in vitro and in vivo. We have also addressed necessary regulatory issues, secured ethical approvals, and have held regular consortium-wide meetings. We have also been pro-actively communicating and disseminating our project and research outputs. Our project website ( and social media accounts (STARSTEM H2020 on Twitter, LinkedIn, ResearchGate) are regularly updated and we have issued press releases, promotional materials, and presented STARSTEM at numerous conferences and events.
The STARSTEM nanostar: We have optimised our synthesis protocol to produce, with high yield and reproducibility, optimal gold nanostars resonant at around 1064 nm. This contrast medium will absorb light at ideal wavelengths for OAI and help ensure that we attain images at unprecedented depth, with excellent sensitivity, and can identify and track our targets. We have also scaled-up the production process in order to deliver sufficient product for preclinical research.
Cell production and OA: Nanostars will be administered for in vitro and in vivo models of OA. Production of our MSCs and MSC-derived EVs has also been established. Through optimisation of a novel medium supplement, we have improved proliferation rates when culturing human MSCs. We have labelled MSCs and EVs with nanostars and have assessed the effects of this labelling process on the functional properties of the cells. Labelled cells are being used in in vitro and in vivo imaging studies.
Imaging: MSOT, a state-of-the-art OAI system ( and MRI are used to visualise and monitor the activity of the MSCs and EVs. Imaging protocols have been defined and we have developed software to analyse the data. We imaged a human finger and a sheep knee using OAI and MRI. This helped us to understand how the different imaging modalities can work together. We are developing co-registration algorithms to compare and combine OAI and MRI images. Preliminary studies with nano-sensitive OCT (optical coherence tomography, another highly sensitive imaging modality) have shown that we can detect small structural changes within tissue. In addition, we have defined methods for tracking MSCs containing SPIONs (magnetic nanoparticles) in large animal joints with MRI.
STARSTEM will help scientists and clinicians to understand how stems cells actually work. A key question for regenerative medicine is the nature of the therapeutic agent – do stem cells lead to healing directly or do they communicate with the body to trigger healing at a distance? This means looking at where they go and how quickly they get there and looking at how healing occurs over time. The STARSTEM approach will be used in vitro and in vivo, from the sub-cellular to whole-animal scale. This will help clarify how and why cell therapies work and provide evidence that can facilitate regulatory approval. The next step for nanostars will be to pass through the Clinical Trial process. After the project is completed, we will apply for such a trial, in order to examine nanostars with labelled cells in action.
STARSTEM has already made progress towards achieving its expected impacts. We are developing a novel and highly sensitive nanotechnology-based imaging approach that will allow for the monitoring of cellular transplants. STARSTEM will have a profound impact on regenerative medicine research and future clinical practice, because it will for the first time enable in vivo tracking of the MSC and EV survival, engraftment, movement, and function, over extended periods and at clinically-relevant depths. The labelling of MSCs and EVs with nanostars will enable us to track and monitor their activity over time and in vivo. OAI is non-invasive and non-traumatic. This means that it can generate high-resolution images deep inside tissues without harming the patient or study subject in any way. It also means that the same subject can be imaged repeatedly and over time, enabling a complete picture of the healing process to emerge.
STARSTEM’s innovation focus is firmly on better therapy through regenerative medicine – the use of cell therapies to cure previously intractable diseases. The results of the project will have extensive benefits for the partners involved and also for the broader European research community.