Tunable hydrogel—Nanoparticles release system for sustained combination therapies in the spinal cord

• PMMA NPs were prepared by emulsion free radical polymerization.
• NPs were loaded in chemical cross-linked hydrogels to guarantee suitable drug release profiles.
• Different sized NPs were loaded in different entangled hydrogels to create a tunable material library.
• Mathematical model provides a complete understanding of material library behavior.
• In vivo studies were performed to confirm in vitro release kinetics.

Poly(methyl methacrylate) (PMMA) nanoparticles (NPs) were prepared by emulsion free radical polymerization. NPs with controlled dimension, as monitored by dynamic light scattering (DLS) and transmission electron microscopy (TEM), were produced by changing experimental parameters, such as the amount of emulsifier and the monomer feeding mode (batch or semi-batch). Then, different sized NPs (60, 80 and 130 nm) were loaded in polysaccharide-polyacrylic acid based hydrogels, cross-linked by covalent ester bonds between polyacrylic acid (PAA) and agarose chains, with different pore sizes (30, 60, 90 nm). The characteristics of the resulting composite hydrogel-NPs system were firstly studied in terms of rheological properties and ability to release Rhodamine B that presents steric hindrance similar to many neuroprotective agents used in spinal cord injury (SCI) repair. Then, diffusion-controlled release of different sized NPs from different entangled hydrogels was investigated in vitro and correlated with NPs diameter and hydrogel mean mesh size, showing different hindrances to the diffusion pathways. Release experiments and diffusion studies, rationalized by mathematical modeling and verified in vivo, allowed to build a material library able to satisfy different medical drug delivery needs.

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