(570f) Remotely Controlled Magneto-Responsive Polymeric Membranes for Controlled Release of Biomacromolecules

Between 2010 and 2020, FDA has approved 97 new therapeutic proteins with subcutaneous injection as the main route of administration. Stimuli-responsive membranes are an attractive field of research [1], and such membranes as barrier for a drug reservoir could offer an alternative route with high reproducibility and dosing flexibility to increase patient’s compliance. For that purpose, a remotely controlled stimulation of the opening and closing of the barrier membrane’s pores would be the preferred option. Previous own work had demonstrated magneto-responsive membranes with excellent switchable rejection for dextran 2000 kDa [2]. The present work aimed at developing membranes with switchable sieving for much smaller biomacromolecules such as insulin (5.8 kDa).

In the first stage of the project, thermo-responsive pore-filled membranes were developed through a two-steps approach. Polyethersulfone (PES) was used to create via casting of polymer solution and non-solvent vapor induced phase separation (VIPS) a porous support membrane, which was subsequently pore-filled via in situ cross-linking copolymerization with poly(N-isopropylacrylamide) (PNIPAAm) hydrogel that acts as the sieving medium. Membranes demonstrated reversible increase in water permeability by about 380 times in response to increased temperature (from 25 to 40°C). Furthermore, rejection of dextran (4 kDa, which has a comparable Stoke’s diameter to that of insulin) under ultrafiltration conditions decreased from 91% to 10%; diffusion rate increased by a factor of 21. This increase in diffusion rate opens up the possibility of pulsatile biomacromolecules release from a reservoir. As an example, a membrane with a radius of 2 cm (12.6 cm²) could deliver from a reservoir the average insulin daily requirement in 2 hours of membrane stimulation.

In the second stage of the project, to add remote control functionality, iron oxide nanoparticles as “nanoheaters” were incorporated via adapted casting and VIPS conditions into the porous PES-based support to create nanohybrid membranes. In response to an external alternating magnetic field (AMF), nanohybrid membrane temperature increases very quickly from 25°C to values far beyond the hydrogel volume phase transition temperature (33°C). Subsequent functionalization under conditions adapted to the modified structure of the base membrane resulted in PNIPAAm pore-filled nanohybrid membranes that demonstrated reversible thermo-responsive changes in water permeability as well as dextran ultrafiltration and diffusion rate, very similar to the only PES-based pore-filled membranes. Furthermore, by AMF activation of the nanoheaters in the PNIPAAm pore-filled nanohybrid membranes, the remotely controlled efficient switching of the membrane from a “closed” to an “open” state for could be shown for both dextran (4 kDa) and insulin.

Overall, highly responsive remotely controlled membranes for controlled release of biomacromolecules as small as insulin have been established. To the best of our knowledge, for the first time in literature such performance is to be reported.

[1] D. Wandera, S. R. Wickramasinghe, S, M. Husson, Stimuli-responsive membranes, Journal of Membrane Science, 2010, 357, 6-35.

[2] X. Lin, R. Huang, M. Ulbricht, Novel magneto-responsive membrane for remote control switchable molecular sieving. Journal of Materials Chemistry B, 2016, 4, 867-879.