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NanoSTARS imaging for STEM cell therapy for arthritic joints

Periodic Reporting for period 1 - STARSTEM (NanoSTARS imaging for STEM cell therapy for arthritic joints)

Reporting period: 2018-01-01 to 2019-06-30

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 the treatment of 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 and over extended periods. There is limited knowledge about their distribution in the body 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 one of the most prevalent diseases worldwide, with OA affecting around 10% of the global population and around 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 and in STARSTEM we use MSCs and EVs. MSCs are a type of cell which can be isolated from the mix of cells which comprise the bone marrow. EVs are tiny sub-cellular fragments of the MSCs and have been implicated in slowing OA development and treatment of the disease. MSCs and EVs are thought to help trigger healing and support tissue repair in the body. We label MSCs and EVs with star-shaped nanoparticles, nanostars, that produce a contrast signal and will help enable us to track their movement and monitor their healing function with OAI and MRI imaging modalities.
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 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. During the first 18 months of the project, STARSTEM has made significant progress on cell production; nanostar design and production; labelling of cell products; and image technology development. We have also been pro-actively communicating and disseminating our project and research outputs. During this period, we have established our project website (starstem.eu) and social media accounts (STARSTEM H2020 on Twitter, Facebook, and LinkedIn). We issued press releases, promotional materials, and presented STARSTEM at numerous conferences and events.
During this project period, we have optimised the design of our nanostar, ensuring that this contrast medium will absorb light at ideal wavelengths for OAI. This will 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 pre-clinical research. 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. Labelling of our cell products with nanostars also began. We have successfully labelled MSCs with nanostars and have assessed the effects of this labelling process on the functional properties of the cells. This is a key enabler for our pre-clinical in vivo research.
Imaging protocols have been defined, and 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 as well as visualise submicron alterations to the structure of MSCs and/or the medium/matrix. In addition, we have defined methods for tracking MSCs containing SPIONs (magnetic nanoparticles that are conjugated to our nanostar) in large animal joints with MRI.
Much of the preparatory work for data analysis and software development was carried out, including the establishment of our data storage and sharing platform. An early study, where we imaged a human finger using OAI and MRI, was carried out to understand how the different imaging modalities can work together. This will facilitate the development of co-registration algorithms to compare and combine OAI and MRI images.
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.
In the first reporting period, STARSTEM has already made progress towards achieving its expected impacts. In particular, important milestones in the project include optimisation of our nanostar design, production of MSCs and the definition of protocols to isolate EVs from MSCs, the labelling of these cell products with nanostars, as well as development of imaging algorithms and establishment of our data service.
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. Our approach combines nanostars as a contrast agent with a state of the art OAI platform (MSOT https://www.ithera-medical.com/) and will be validated in pre-clinical models of OA. 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 imaging deep inside tissues without harming the patient or study subject in any way (e.g. no need to puncture the skin). 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. STARSTEM has already contributed to an increase in the innovation capacity of the partners involved.
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