WP4: Piezoelectric nanoparticles and US stimulation set-up
Task 4.1: Development of US stimulation set-up (SSSA)
As already known, the periodic application of low-power US over relatively long periods of time causes local mild hyperthermia, thus increasing the afflux of blood to the targeted organ.
This “direct” effect generated by US will be associated with two additional “mediated” effects, namely piezoelectric response of nanoparticles embedded in the coating (thus implying electrical stimulation of neurons) and drug/neurotrophic factor release (triggered by the increase of temperature, by electrical or mechanical phenomena). US parameters (intensity, frequency and duration of the stimulation) will be adjusted (also depending on the material structure and nanoparticle properties) in order to maximize such direct and indirect beneficial effects on the peripheral nerves. The attenuation due to the intermediate tissues during in vivo stimulation will be obviously a factor to consider in this task: proper models and ad hoc experimental design will help in optimizing the US parameter estimation. To face these issues, SSSA will exploit an already established knowledge and dedicated equipment, deriving from experimental work on sonothrombolysis. It is worthy to note that SSSA is the coordinator of a recently launched STREP FP7 Project, centered on the use of focused ultrasounds for non-invasive therapy (FUTURA project, grant agreement 611963). This will highly facilitate the development of a dedicated set-up for US stimulation of the multifunctional coating.
Task 4.2: Functionalization of piezo nanoparticles (SSSA)
Within this task, SSSA will choose, functionalize and embed in the hydrogel active nanoparticles showing piezoelectric properties. The scientific hypothesis behind is that properly tuned external US stimulation will determine an electrical response of the embedded particles, with beneficial effects on the peripheral nerves.
Previous work at SSSA demonstrated that it is possible to exploit boron nitride nanotubes (piezoelectric nanoparticles) as nanovectors to carry electrical/mechanical signals on demand within a cellular system. Electrical stimuli were conveyed to neurons or muscle cells after nanoparticle internalization, using ultrasounds as outer “wireless” mechanical source. Other works of the same group demonstrated that barium titanate nanoparticles (also showing piezoelectric properties) positively influenced cell behavior, even if they were embedded in the substrate and not internalized by cells.
Furthermore, it is known that ultrasounds can trigger or enhance drug release from different types of matrices, due to mechanical and thermal phenomena. It is rather unexplored if piezo-mediated electrical events could also trigger or enhance drug release from engineered matrices.
Piezoelectric nanomaterials with tuned chemical and physical properties should be stably embedded in the hydrogel layer. Chemical functionalization (e.g. by protein or polymer wrapping) will facilitate their stable inclusion in the hydrogel matrix (developed within WP3) and will avoid negative interference with the entrapped drugs/neurotrophic factors. Physical properties, such as the resonance frequency, will obviously directly affect the development of the ultrasound stimulation set-up, as previously described. Possible long-term adverse effects are always a risk, when nanoparticles are deployed within the human body. However, in our case, the stable entrapment of nanoparticles within the hydrogel matrix and the non-degradable nature of the hydrogel will minimize the release of nanoparticles from the device, thus also minimizing long-term risks