Bicolor imaging with x-Rays to Evaluate A Repair Kit THRroUgh dedicated labelling of stem cells and hydrogel – BREAKTHRU

Stem cell therapies are currently evaluated in many clinical trials. For efficient integration between the grafted cells and the host, stem cells may be embedded within a bio-engineered hydrogel thus forming a “repair kit”. To increase the chances of success in future clinical trials, the optimal formulation of such repair kit should be defined not only in-vitro but also and mostly in well-designed in-vivo studies. Therefore, there is a crucial need to develop “bi-color imaging”, allowing the distinct and simultaneous in-vivo monitoring of stem cells on the one hand and cell-embedding hydrogels on the other hand. The challenge is to propose a solution involving clinically compliant imaging techniques, in order to foster the clinical transfer of the obtained theranostics tools.

Recently, a fundamental shift in CT technology occurred with the introduction of dual-energy CT (DECT) or “spectral CT” into clinical CT scanners. Advances in detector technology have extended the DECT approach by adopting photon-counting detectors rather than energy-integrating detectors. Spectral photon-counting CT (SPCCT) allows selective visualisation and quantification of multiple contrast agents in a single scan by exploiting the K-edge discontinuity in x-ray absorption, a concept coined “K-edge imaging”. This eliminates the need for imaging before and after injection since the location of the contrast media can be determined solely from a post-injection scan, thus reducing the dose and streamlining both acquisition and post-processing. Up to now, K-edge imaging could be performed only with x-rays from Synchrotron radiations using a technique called K-edge subtraction CT (KES-CT). This technique may be applied in patients, however, it is obviously not widely available. The future market entry and penetration into clinical practice of SPCCT is a game-changer. The first SPCCT in the world that was fast enough to allow in-vivo imaging, developed by Philips, was installed in Lyon in 2015 at the imaging platform Cermep thus opening an avenue for widespread multicolor imaging in patients.

The core objective of BREAKTHRU is to develop bi-color imaging using SPCCT with the aim of monitoring during several weeks the fate of stem cells on one hand and of cell-embedding hydrogels on the other hand, after in-situ transplantation in rodent models of chronic diseases. To demonstrate the wide potential of our imaging approach, we have selected two relevant clinical applications for which the biodistribution course of cells and hydrogel will differ: osteoarthritis and ischemic stroke. To design the repair kits, we will use clinical grade adipose-derived stem cells that we will label with gold nanoparticles and hyaluronic acid hydrogel that we will label with iodine. Once finalized, the repair kits will undergo thorough assessment of safety and potential toxicity to make sure that labelling of cells and hydrogel does not compromise therapeutic activity. We will use phantom and rodent studies to develop and validate the bi-color imaging tools. Robust validation will be obtained by imaging animals in-vivo back-to-back using SPCCT and KES-CT. Our ambition is to provide the proof of concept that long-term monitoring of each component of the repair kit is: (i) feasible in a single SPCCT scan and (ii) highly valuable for the personalised evaluation of therapeutic efficacy, and complementary to health outcome endpoints and multi-parametric MRI follow-up of tissue repair. The integration of advanced imaging technology within new stem cell therapies is expected to have important impacts in the field of regenerative medicine and by extension, major socio-economic impacts in the fields of stroke and osteoarthritis, by reducing the burden of these diseases both for patients and for healthcare systems, thanks to these new therapies and their companion imaging tools.