Periodic Reporting for period 1 - Piezo4Spine (Piezo-driven theramesh: A revolutionary multifaceted actuator to repair the injured spinal cord)
Periodo di rendicontazione: 2023-01-01 al 2023-12-31
Piezo4Spine aims to develop a novel multifactorial therapy for spinal cord injury (SCI) conceived as a disruptive platform enabling unprecedented multiscale actuation to drive functional neural repair by more accurately tackling SCI complexity. It originally relies on the pivotal role that mechanotransduction plays in the physiology and physiopathology of tissue and organ functions, never explored before for SCI. We will develop a 3D bioprinted mesh containing nanocarriers with therapeutic agents acting at two pivotal aspects of neural repair: mechanotransduction and inhibitory scarring using gene therapy strategies. Bioactive nanocarriers will base on cutting-edge nanoparticles whose release will be electrically triggered on-demand via wireless powering. Such 3D-theramesh offers a novel and exceptionally robust biomaterial for delivering agents at the lesion, controlling time and dose. Current advances on SCI therapies focus on rehabilitation, cell transplantation, drugs, biomaterials, and/or electrical stimulation. Although leading to partial sensory/motor recovery, chronic functional deficits limit daily living activities and shorten live expectancy in SCI patients, as they fail to promote successful axon regeneration at the lesion and awake lost functions. By a multidisciplinary consortium combining scientific, technological, clinical and industrial partners enriched by their interdisciplinarity, we envision to overcome limitations of current technologies by tackling multiple cellular targets involved in neural regeneration after SCI with a balanced combination of therapeutic interventions able to optimally promote functional recovery. These radical science-to-technology breakthroughs could enable, if successful, novel technologies and therapies for SCI and many other neural and non-neural pathologies in which some, but not necessarily all, of these targets are involved. Gender dimension will be implemented by ensuring that findings apply to society as a whole.
Along this first year of the Piezo4Spine project, all work packages (WP) except for WP5 have been initiated, with all partners actively working in their respective tasks. Specifically, two kinds of nanocarriers have been designed and are under investigation for their capacity to load and deliver specific cargos. These nanocarriers have been already incorporated into preliminary versions of freeze-casted and 3D-printed meshes, exploring different natural polymers. A specific 3D bioprinter is being designed to serve the objectives of the project. The physico-chemical properties of all these materials, both in their single or combined forms, have been carefully characterized including nanomechanical properties by atomic force microscopy. Both types of nanocarriers and some of these hybrid meshes have been already tested in-vitro with primary neural cells, primary meningeal and dermal fibroblasts, and immune cell lines. A specific hybrid mesh with promising results in-vitro has been also tested in preliminary in-vivo studies in paralyzed rats. The exploration of motor training routines is being also initiated. Behavioural, resonance magnetic imaging, electrophysiological, and histological methods are being stablished to serve WP4 and WP5 along the project.
Piezo4Spine has already provided some promising results that are beyond the state of the art. Specifically, we have designed novel magnetically responsive meshes loaded with novel therapeutic nanocarriers based on superparamagnetic iron oxide nanoparticles that are mechanically soft and highly compatible with primary neural cells in vitro (2 publications). We have also developed polymeric nanoparticles able to control the reactivity of fibroblasts by the delivery of specific mRNA molecules (1 patent). The first 3D-printed polymer meshes loaded with these nanoparticles have been also fabricated. Physico-chemical and biological characterization of these 3D matrices still provided suboptimal results. A first preliminary version of the wireless stimulation device has also been attained in WP3 (1 publication). Primary neural cells have shown biocompatible responses when in contact with the nanoparticles and magnetic hydrogels developed. All these results are highly promising and encourage further investigation as planned in the GA.