Periodic Reporting for period 2 - Piezo4Spine (Piezo-driven theramesh: A revolutionary multifaceted actuator to repair the injured spinal cord)
Periodo di rendicontazione: 2024-01-01 al 2025-06-30
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 these 30 months, the Piezo4Spine consortium has actively worked in all workpackages, with an outstanding complementarity and interdisciplinary understanding. Work performed and main achievements are broken down as follows:
- WP1: Three kinds of nanocarriers have been successfully designed and optimized as therapeutic cargos. Intensive work on 3D meshes development has also generated a few versions of therapeutic meshes under investigation for active nanocarriers loading. Careful physicochemical characterization of all these materials has been carried out. Release studies under electrical and magnetic stimulation have been initiated.
- WP2: Nanocarriers and 3D freeze-casted and 3D-printed meshes are being intensively explored for in vitro biocompatibility, biodegradability and biofunctionality. These biological studies are covering the response of a variety of cells with relevance for neural repair (primary neural cells including neurons and glial cells, primary meningeal fibroblasts, and immune cell lines including macrophages and microglial cells).
- WP3: Electrode design for on-demand release from the 3D-theramesh has significantly advanced during this period, with an almost completely biodegradable microelectrodes array being developed that is under intensive investigation. The microelectrode array has been implanted in SCI models for stimulation and recording in acute. Much advance has been done also in the understanding of the electronic processing of the signals.
- WP4: Motor training routines in paraplegic rats have been extensively investigated and implemented. Experimental models of spinal cord injury under examination include: cervical hemisection at C6 and complete transection at T9-T10. Behavioural, electrophysiological, and histological methods are being stablished.
- WP5: Several 3D meshes (partially or fully therapeutic) are under examination in cervical hemisected rats (in vivo). Male rats are being used to date, but studies with female rats have been also initiated. Other SCI models will be implemented as result of useful feedback from clinical neurosurgeons that have been contacted.
- WP1: Three kinds of nanocarriers have been successfully designed and optimized as therapeutic cargos. Intensive work on 3D meshes development has also generated a few versions of therapeutic meshes under investigation for active nanocarriers loading. Careful physicochemical characterization of all these materials has been carried out. Release studies under electrical and magnetic stimulation have been initiated.
- WP2: Nanocarriers and 3D freeze-casted and 3D-printed meshes are being intensively explored for in vitro biocompatibility, biodegradability and biofunctionality. These biological studies are covering the response of a variety of cells with relevance for neural repair (primary neural cells including neurons and glial cells, primary meningeal fibroblasts, and immune cell lines including macrophages and microglial cells).
- WP3: Electrode design for on-demand release from the 3D-theramesh has significantly advanced during this period, with an almost completely biodegradable microelectrodes array being developed that is under intensive investigation. The microelectrode array has been implanted in SCI models for stimulation and recording in acute. Much advance has been done also in the understanding of the electronic processing of the signals.
- WP4: Motor training routines in paraplegic rats have been extensively investigated and implemented. Experimental models of spinal cord injury under examination include: cervical hemisection at C6 and complete transection at T9-T10. Behavioural, electrophysiological, and histological methods are being stablished.
- WP5: Several 3D meshes (partially or fully therapeutic) are under examination in cervical hemisected rats (in vivo). Male rats are being used to date, but studies with female rats have been also initiated. Other SCI models will be implemented as result of useful feedback from clinical neurosurgeons that have been contacted.
Piezo4Spine is providing many promising results that are beyond the state of the art, as listed below:
1. Novel therapeutic nanocarriers based on superparamagnetic iron oxide nanoparticles (1 paper + 1 manuscript under review + 2 manuscripts in preparation + 1 eventual patent).
2. Novel therapeutic nanocarriers based on polymeric nanoparticles (1 patent + 2 manuscripts in preparation).
3. Several partially and fully therapeutic 3D meshes (2 papers + 2 manuscripts in preparation + 1 eventual patent).
4. Knowledge in the understanding of cell mechanobiology and atomic force microscopy measurements processing (3 papers).
5. An almost complete biodegradable microelectrodes array specifically designed to brain and spinal cord injury applications, already implanted in SCI models for stimulation and recording in acute (2 publications + 1 manuscript under review + 1 manuscript in preparation + 1 eventual patent).
6. A clinically inspired motor training routine proved to enhance neural repair at the injured spinal cord (1 manuscript under review + 1 manuscript in preparation).
All these results keep being highly promising and encourage further investigation as planned in the GA.
1. Novel therapeutic nanocarriers based on superparamagnetic iron oxide nanoparticles (1 paper + 1 manuscript under review + 2 manuscripts in preparation + 1 eventual patent).
2. Novel therapeutic nanocarriers based on polymeric nanoparticles (1 patent + 2 manuscripts in preparation).
3. Several partially and fully therapeutic 3D meshes (2 papers + 2 manuscripts in preparation + 1 eventual patent).
4. Knowledge in the understanding of cell mechanobiology and atomic force microscopy measurements processing (3 papers).
5. An almost complete biodegradable microelectrodes array specifically designed to brain and spinal cord injury applications, already implanted in SCI models for stimulation and recording in acute (2 publications + 1 manuscript under review + 1 manuscript in preparation + 1 eventual patent).
6. A clinically inspired motor training routine proved to enhance neural repair at the injured spinal cord (1 manuscript under review + 1 manuscript in preparation).
All these results keep being highly promising and encourage further investigation as planned in the GA.