ReWIRE will combine innovative translational neurotechnologies and rehabilitation interventions for the repair and restoration of neurological functions following injury of the spinal cord (SC). The proposed research program will equip next-generation scientists with unique skills to develop disruptive therapeutic solutions for patients with paralysis. Recent technological breakthroughs have triggered a paradigm shift in the conception of therapies aimed to restore function after spinal cord injury (SCI). Novel drug delivery systems and biomaterial bridges have been engineered to reduce secondary injury and scarring, to stimulate and guide regenerating nerve fibres across the lesion site, and to promote functional reconnection with intact tissue. Additionally, neuromodulation therapies can reactivate spinal circuits below a SCI, allowing people with chronic paralysis to regain voluntary control of walking. In conjunction with rehabilitation, neurological recovery was promoted that persisted without neuromodulation, suggesting a rewiring of the SC as demonstrated in preclinical models. To bypass an injury, neuromodulation has been linked to brain signals to re-establish cortical control over spinal circuits by employing electrical nerve stimulation and robotic systems. Advances in robotics are significantly augmenting the impact of neurorehabilitation by inducing new natural “wired” connections. The aim of ReWIRE is to leverage all these technical and therapeutic breakthroughs in the framework of multiple PhD projects that will continuously interact to converge toward effective combinatorial treatments for SCI. ReWIRE will focus on three inter-woven objectives: i) establish an international, interdisciplinary, and intersectoral educational network, ii) build an SCI clinical data platform, and, iii) position Europe at the forefront of therapy for SCI.

To date, light has been employed as a widespread trigger to achieve control over the activity of drugs and protein function establishing the fields of photopharmacology and optogenetics, respectively. Both techniques led to promising new therapies, the elucidation of brain function or understanding of neural disorders. However, serious limitations resulting from the low penetration depth of light into tissues are severely hampering progress in these fields. In contrast to photons, ultrasound deeply penetrates tissue and can be applied with sub-millimeter resolution and consequently has been widely established in the clinic over many decades for therapy and diagnostics. In this ERC Advanced Grant, I will develop a radically new approach to control the activity of drugs, proteins and genes by biocompatible ultrasound. Polynucleic acid carriers, which can bind a wide variety of bioactive payloads, will be designed to be sensitive to different ultrasound sources, which can be applied in clinical settings and do not harm cells or tissues. Upon ultrasound irradiation, these carriers liberate their bioactive payloads by mechanochemical principles to switch on drugs and control cellular functions. To achieve this aim, I will: investigate the effect of ultrasound (US) on nucleic acid architectures; study the loading of polynucleic acids with different payloads and their release by US; develop a technology platform to activate small molecule drugs, proteins and oligonucleotides; and showcase the huge potential of these technologies for cancer immunotherapy, diabetes research and tissue engineering. This project will boost sonopharmacology and sonogenetics. Its outcomes will enable spatiotemporal control of drug action to minimize side effects in pharmacotherapy like cancer. The remote controlled orchestration of protein and gene function by US will strongly advance medicine and the life sciences by answering fundamental questions in these fields.

The limitations of current in vitro tissue models pose a significant challenge in drug discovery and personalized medicine, leading to inefficiencies and unreliability in preclinical testing. These shortcomings result in high costs and prolonged timelines for drug development, straining resources and delaying patient access to innovative treatments. This is mainly due to the currently available cell and tissue models based on flat petri dishes and isotropic hydrogels, which fail to accurately represent the anisotropic structures found in native tissues leading to unreliable preclinical results. Animal models, although considered the gold standard, raises ethical concerns and introduces significant differences compared to human tissues. To address these shortcomings, we have developed a hydrogel system that can be used to fabricate 3D culture models with oriented structures using AnisoPlate. The AnisoPlate is a handheld magnetic device for providing the required external magnetic field in culture plates for the orientation of the rods. The hydrogel system consists of rod-shape elements that are made magneto-responsive by encapsulating superparamagnetic iron oxide nanoparticles (SPIONs). When exposed to low external magnetic fields (in the millitesla range) provided by the AnisoPlate, these rods align in the direction of the field and can be assembled into 3D macroporous oriented constructs mimicking the anisotropic architecture of human tissues. Our solution holds promise not only for researchers in drug discovery, tissue engineering, and regenerative medicine but also for pharmaceutical industries seeking physiologically relevant in vitro models for more accurate preclinical studies, contract research organizations (CROs) aiming to enhance their efficacy in high-throughput screening, and ultimately patients who stand to benefit from accelerated and improved drug development processes leading to innovative treatments.

Polymeric materials are ubiquitous in our daily lives but they have a predominantly fossil origin, with low degradability at their end-of- life. Transitioning to a circular polymer economy requires a rethinking of the entire value chain, from the raw materials, tools, and processes used to polymer design degradation and recycling. Enzymes are eco-friendly and sustainable tools that tackle many industrial applications. However, biocatalysis in the polymer field remains mostly unexplored due to i) enzymes’ high cost and low stability under reaction conditions, ii) enzymes’ inefficiency in converting bio-based monomers into cost-effective building blocks, and iii) lack of knowledge in key enzyme-polymer interactions that can control the final polymer performance and degradability features. Computational tools have shown immense power to revolutionize the field of enzyme engineering in a time and cost effective way. However, there is currently a clear lack of researchers combining computational and experimental skills, capable of determining future directions for the optimization of biocatalytic processes for the sustainable molecular design of polymers. To foster the transition to a bio-based polymer industry, COMENZE aims to develop enzymatic strategies for improving the eco-design and development of future sustainable polymers. This will be achieved by combining cutting-edge computational and experimental approaches for enzyme discovery and engineering through in-silico modeling, simulation, and translation of results into wet labs to validate enzymatic reactions. COMENZE will train the next generation of researchers by equipping 10 DCs with the skills to revolutionize the polymer circularity by delivering new optimized enzymes and bioprocesses, newly identified bio-based building blocks, and functionalized polymers with innovative bio-upcycling and biodegradation end-of-life options.