Technology-driven combinatorial therapy to rewire the spinal cord after injury

Project Information

ReWire

Grant agreement ID: 101073374

DOI

10.3030/101073374

EC signature date 15 July 2022

Start date 1 January 2023

End date 31 December 2026

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 2 666 836,80

Coordinated by

DWI LEIBNIZ-INSTITUT FUR INTERAKTIVE MATERIALIEN EV
Germany

Periodic Reporting for period 1 - ReWire (Technology-driven combinatorial therapy to rewire the spinal cord after injury)

Reporting period: 2023-01-01 to 2024-12-31

Summary of the context and overall objectives of the project

Traumatic spinal cord injuries (SCI) are primarily caused by mechanical damage to the central nervous system, with road traffic accidents and falls as main causes. They result in impairment of motor, sensory, and autonomic functions, thus requiring tailored and personalised treatment strategies. Plasticity can result in new connections and neural circuits, contributing to a compensatory recovery of function. There is substantial progress in understanding the cascade of cellular and molecular events, but there are still no effective interventions that mitigate the extent of damage, and current treatment strategies have proven insufficiently effective in patients. Conventional therapies focus on resolving individual aspects of SCI, thereby neglecting synergies to tackle multiple targets simultaneously. Technological advances in drug delivery systems, biomaterials, electronics, and robotics have resulted in novel developments to regain lost function after SCI. ReWIRE is evolving and combining these technological advances. The overall goal is to translate combinatorial SCI therapies from bench to bedside in a timely manner, thereby improving the quality of life and reducing societal burden.
In ReWIRE, the Doctoral Candidates are exposed to basic SCI science and repair strategies, as well as cutting-edge technologies in related scientific fields. A special focus is set on personalised therapies, including tailored rehabilitation programs. To achieve this, ReWIRE is merging the following three key developments:
i) reactivation, stimulation, and attraction of nerve growth using drug delivery systems
ii) support and guidance of nerve growth with biomaterial bridges
iii) enhancement and stabilization of nerve growth by inducing plasticity via electrical stimulation, robotics, and rehabilitation
ReWIRE is set up to equip next-generation scientists with unique skills to develop ground-breaking therapeutic solutions for patients with SCI. ReWIRE’s first objective is to establish an international, interdisciplinary, and intersectoral educational network that develops and links high-tech routes into new personalized, combinatorial approaches to rewire the spinal cord. The second objective is to build a clinical data platform for SCI. The third objective is to position Europe at the forefront of therapy for SCI.
The training and research parts are focused on developing the next generation specialists and technologies in the European Research Area. Specifically, ReWIRE aims to establish meaningful functional recovery by combining axonal regrowth and reconnection with new neuronal circuits, controlled by the brain and boosted by neuromodulation. The overall goal is to translate combinatorial SCI therapies from bench to bedside in a timely manner, thereby improving the quality of life and reducing societal burden. The convergent approach will lead to combinatorial therapies to repair the spinal cord after injury, which, to date, has not been successful using individual therapies.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The main scientific achievements within the first years of ReWIRE regarding drug delivery systems involve the identification of novel regenerative targets, in particular the elucidation of the role of a unique metabolic pathway in axonal regeneration. The treatment with modified immune-evasive viral vectors is showing great promise in improving the functional outcome in models of spinal cord trauma in vivo. The research performed in the field of biomaterial bridges, has led to the development of novel hydrogels as well as macroporous microgel constructs, and microgels loaded with therapeutic molecules. Degradable mechanical micoconnector sytems to bridge large tissue defects after severe SCI have been fabricated and undergone in vitro tests before their effectiveness will be tested in extensive analyses in future experiments in vivo. Using innovative screening techniques, peptides that mimic the functions of cell binding proteins have been identified. These peptides will be combined with the bridging materials in order to facilitate cell and nerve attachment, proliferation and migration. An in vitro model of the human spinal cord has been developed, with which an injury can be induced and different treatment methods can be assessed, which could significantly improve the investigation of central nervous system injuries and speed up the development and testing of SCI therapies. So far, a platform that sustains the growth of human neural cells long term (>3 months) has also successfully been developed. This will allow the ReWIRE team and eventually other researchers to assess the functionality of the connection between two organoids before injury, after injury, and after treatment, thus providing a metric for assessing neural regeneration. The project parts focusing on electrical stimulation, rehabilitation and robotics have contributed significant insight regarding both basic SCI research and translational approaches for patient rehabilitation. Anatomical mapping has idenfied "hotspots" critcal for bladder control in the lumbosacral spinal cord, addressing a critical unmet need in the field of SCI rehabilitation. Wearable sensors to detect movement intention in patients are evaluated in clinical settings in an ongoing SCI trial. The performance of defined algorithms is analyzed using electrodes to restore fine hand manipulation in tetraplegic patients. Innovative exosuits for finger and arm movements have been developed and undergone first trials. Implantable electrodes for brain-controlled epidural stimulation have been developed and implanted into the first patients to explore their efficiency to successfully restore voluntary arm and hand movement. Finally, non-invasive spinal cord stimulation methods have been developed as alternatives to the invasive approaches. Finally, ReWIRE has also made significant progress in the data mining of clinical SCI data and in the development of data-driven prediction for SCI outcomes. These results will significantly improve future (personalized) therapy design for spinal cord injured patients.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

ReWIRE has led to a new understanding in the field of biomedical material science, SCI, SCI rehabilitation, and SCI data mining, which significantly advances existing knowledge and current SCI treatment paradigms. ReWIRE has achieved the development of novel methods (e.g. for SCI data-driven outcome prediction), advanced devices and protocols for SCI patient rehabilitation, and the development of innovative biomaterials and coating technologies that will allow for more efficient and/or more accurate SCI research and therapy development. ReWIRE brings together researchers from different disciplines, such as biology, engineering, material science, physics, medicine and industry, to generate new insights in spinal cord injury research and therapy development. The unique overarching approach can enable breakthrough solutions for the very complex condition SCI (a medical area where boundaries between fields are traditionally defined) that would be impossible within the constraints of individual disciplines.