Abstract: BACKGROUND: Gold nanoparticles are of great significance in the development of multifunctional transdermal drug delivery systems. Smaller gold nanoparticles can penetrate the dermis through the intercellular pathway, but are limited to their easy agglomeration and colloidal morphology, which makes it difficult to exert effects on low delivery efficiency.
OBJECTIVE: To develop an ultrasound-optimized hydrogel delivery system by combining phase change nanodroplets with bio-adhesive hydrogel for percutaneous delivery of gold nanoparticles.
METHODS: The ultrasound-responsive nanodroplets loaded with gold nanoparticles were prepared by the emulsion solvent evaporation method and loaded into the polydopamine-modified methylacryloyl gelatin hydrogel to prepare a composite hydrogel scaffold. The structure and chemical composition of the ultrasound-responsive nanogold carrier were characterized. The microstructure, porosity, permeability, rheology, in vitro hemostasis, and antibacterial properties of the composite hydrogel were characterized. The cell compatibility of the hydrogel scaffold was evaluated by live/dead staining, and the optimization effects of low-intensity pulsed ultrasound on the permeability, porosity, and mechanical properties of hydrogel were evaluated.
RESULTS AND CONCLUSION: (1) Transmission electron microscopy and ultraviolet-visible spectroscopy proved the successful construction of nanogold carriers. The particle size and potential results demonstrated that the synthesized nanoscaled ultrasonic responsive carrier had good stability. (2) Live/dead cell staining proved that the prepared composite hydrogel scaffold had certain biocompatibility. (3) Scanning electron microscopy exhibited that the prepared composite hydrogel scaffold had a porous network structure, and numerous pores of about 2 μm appeared inside the macropores after the addition of nanodroplets and ultrasonic irradiation. The permeability experiment displayed that low-intensity pulsed ultrasound could optimize the porosity and permeability of hydrogel materials. The hemostatic performance of the composite hydrogel scaffold was better than that of the hemostatic sponge and polydopamine@methylacrylylated gelatin hydrogel scaffold. Under the irradiation of low-intensity pulsed ultrasound, the composite hydrogel scaffolds had good antioxidant effects and antibacterial properties. (4) Thermal imaging results manifested that gold nanoparticles were encapsulated in ultrasound-responsive nanobubbles, and more uniform dispersion could be obtained under ultrasonic excitation. (5) The results of the mechanical property test demonstrated that the storage modulus of the hydrogel increased before and after loading gold nanoparticles-nanodroplets, which showed stronger mechanical properties. The elongation at break was 122%, and the ductility was better than that without gold nanoparticles-nanodroplets (P < 0.05). (6) These findings indicate that the composite hydrogel scaffold has good biocompatibility, antibacterial property, oxidation resistance, and hemostatic effect.

Key words: tissue engineering, ultrasonic microbubble, low-intensity pulsed ultrasound, gold nanoparticle, methylacryloyl gelatin, transdermal drug delivery