DeLIVER will train a new generation of ESRs in the development and application of newly developed high speed and high resolution imaging tools in biomedical research. ESRs will be cross-pollinated with concepts and skills in physics and biomedicine, in particular in super-resolution optical imaging (a.k.a. optical nanoscopy), analytical image reconstruction, and optical micro-manipulation methods. These skills are applied to reveal for the first time the function and dynamics of nanosized pores in endothelial cells (EC) that present the main barrier between the blood and vital organs for human physiology, such as the liver, brain, kidneys, and the eyes. Very little is known about the extremely important physiological function of these unique structures and their role in the transfer and/or clearance of metabolites and pharmaceuticals to vital organs. The current generation of optical nanoscopes, however, is rather slow and can only be applied to isolated, typically fixed (i.e. dead) cells rather than biomedically relevant tissues. Also, newcomers to the field need to familiarize themselves with a whole new set of potential problems that might arise in the use of optical nanoscopy, such as image reconstruction-related artifacts to name just one example.This is an area of research where European enterprises are very active. Excellent training in new scientific and complementary skills, combined with international and intersectoral work experience, will instil an innovative, creative and entrepreneurial mind-set in DeLIVER's ESRs, maximising economic benefits based on scientific discoveries. These specialised, highly trained, and mobile ESRs will have greatly enhanced career prospects. The training in novel physical methods with highly relevant experience in the biomedical sciences will allow them to confidently navigate at the interface of academic, clinical and private sector research.

Cancer treatment faces a major problem: it ultimately stops working for many patients because the tumor becomes resistant. The cellular origin of relapse is often linked to drug tolerant persister (DTP) cells, which survive treatment and can remain for years. Because of their scarcity and heterogeneity, the detection of DTP cells remains a technological challenge of enormous clinical importance. The objective of REAP is to develop two next generation multimodal imaging systems to reveal DTPs. A triple modal two-photon laser scanning optical coherence photoacoustic microscopy system will be built for the in vitro characterization of cancer organoids. Additionally, a dual-modality optical coherence photoacoustic tomography system will be implemented to visualize tumors in vivo in a mouse model. To enable greatly increased sensitivity and specificity, a new type of contrast agent based on biofunctionalized nanoparticles with tailor-made optical properties will be fabricated to specifically label DTPs. For improved imaging performance, several further technological advancements are targeted. Photoacoustic excitation will be realized using innovative microchip lasers addressing the needs for high-energy pulses, high-repetition rate, and multi-wavelength emission. To achieve the required resolution, novel photoacoustic detectors based on integrated optical micro-ring resonator technology will be developed with the potential to completely replace conventional piezoelectric ultrasound transducers. Furthermore, image acquisition speed will be increased by an order of magnitude with the help of an innovative laser source based on photonic integrated circuits at 780 nm. Finally, real-time data handling will be explored along with deep learning-based automatic analysis algorithms. The combined innovation in laser sources, detector technology, nanoparticles, and deep learning-based algorithms will create radically new imaging solutions reaching numerous applications.