Nanocomposite membranes based on thermosensitive, poly(N-isopropylacrylamide)-based nanogels and magnetite nanoparticles have been designed to achieve “on-demand” drug delivery upon the application of an oscillating magnetic field. On-off release of sodium fluorescein over multiple magnetic cycles has been successfully demonstrated using prototype membrane-based devices. The total drug dose delivered was directly proportional to the duration of the “on” pulse. The membranes were non-cytotoxic, biocompatible, and retained their switchable flux properties after 45 days of subcutaneous implantation.

Drug delivery devices based on nanocomposite membranes containing thermoresponsive nanogels and superparamagnetic nanoparticles have been demonstrated to provide reversible, on-off drug release upon application (and removal) of an oscillating magnetic field. We show that the dose of drug delivered across the membrane can be tuned by engineering the phase transition temperature of the nanogel, the loading density of nanogels in the membrane, and the membrane thickness, allowing for on-state delivery of model drugs over at least two orders of magnitude (0.1-10 µg/ hr). The zero-order kinetics of drug release across the membranes permit drug doses from a specific device to be tuned according to the duration of the magnetic field. Drugs over a broad range of molecular weights (500-40,000 Da) can be delivered by the same membrane device. Membrane-to-membrane and cycle-to-cycle reproducibility is demonstrated, suggesting the general utility of these membranes for drug delivery. KeywordsIron oxide; nanogel; nanoparticles; triggered drug release; on-demand; superparamagnetism Sustained drug release technology has been applied in a wide variety of medical fields1. Many devices are passive, exhibiting release kinetics that are either constant or decreasing over time. However, drug delivery devices that can be repeatedly switched on and off would be optimal for effective treatment of conditions such as diabetes, chronic pain, or cancer. 2 * To whom correspondence should be addressed. Daniel.Kohane@childrens.harvard.edu. † These authors contributed equally to this report. To this end, environmentally responsive ("smart") materials have been developed that can respond to stimuli that are either internal to the patient (e.g. body temperature) or external (e.g. a remotely-applied magnetic field). Temperature-sensitive drug delivery devices have been developed based on the thermoreversible polymer poly(N-isopropylacrylamide) (PNIPAm) 3 , which has been incorporated into implantable hydrogels4 -9, microparticles10, nanoparticles [11][12][13][14] , and surface-grafted polymers [15][16][17][18][19][20][21][22][23][24][25][26][27] . Examples of magnetically-activated materials include superparamagnetic nanoparticles, which absorb power when placed in an oscillating magnetic field and transfer heat to the surrounding medium. These nanoparticles have been used to achieve drug release from polymer scaffolds 28 , sheets 29 , liposomes 30 , microspheres 31,32 , microcapsules 33 , and nanospheres [34][35][36] , typically by mechanical disruption of the drug-biomaterial matrix. However, the quantity of drug contained by most of these "smart" carriers is relatively small, and drug release is often characterized either by a single burst event or inconsistent dosing as a function of triggering cycle. Supporting InformationTo achieve both triggered drug release and consistent dosing, we previously reported composite membranes containing both temperature-sensitive polymer nanoparticles (nanogel) and magnetically activated superparamagn...

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