Nanoengineered platforms for controlled release of factors for the nervous system

Nerve growth factor (NGF) has been well characterized for its essential role in the development and maintenance of neurons both in the peripheral and central nervous systems. Potential therapeutic applications of this protein have been demonstrated in several models of neurodegenerative diseases, including Alzheimer’s.. In particular, external administration of NGF exhibits protective properties for injured neurons, stimulating axonal regeneration, playing a major role in the repair process of peripheral nerve tissue. However, NGF effectiveness in therapeutics is limited by its short biological half-life due to rapid enzymatic degradation in vivo. Therefore, there is an immense need for designing delivery systems that will direct the factor towards injured targets and allow for sustained and prolonged release of NGF. Previously we have shown an engineered setup based on porous silicon that released effectively NGF for a month. Here I will present nanoengineered systems we have developed based on NGF combined with magnetic nanoparticles (MNPs). NGF, a 26-kDa neurotrophin, was conjugated to iron oxide MNPs and directed selectively by external magnets to target sites as injured nerves and retina demonstrating higher resistance of NGF to protease activity, and prolong bioavailability. Then the conjugated MNPs were mixed with collagen gel to establish a 3D platform for neuronal regeneration. Applying magnetic forces actuated movememt of MNPs within the gel leading to the alignment of collagen fibers and MNP aggregation in string structures. We found that through dissolution of MNPs from strings the conjugated MNPs were released over time, allowing for continuous stimulation of neurons. We demonstrated the functionality of the MNP complexes in vitro and in vivo. We showed that following peripheral injury, the administration of the conjugated MNPs stabilized the delivery of NGF for longer periods of recovery. A nerve conduit filled with the gel demonstrated a multifunctional platform. We showed an effective slow release of the MNPs from the macro structures up to several weeks. In a rat sciatic nerve injury model we have demonstrated the promoting effect of the growth factor release on nerve repair. Results demonstrate high reconstruction of the nerve in MNP-NGF group, as well as intra-fascicular architecture restoration.