Leveraging nanochannels for a remotely controllable implantable drug delivery system

This work is focused on the research on how to leverage nanochannels in the eld of Nanomedicine. More speci cally the study of different diffusion regimes at the nanoscale thanks to the close collaboration between the Politecnico di Torino, Turin, Italy, and the Methodist Hospital Research Institute, Houston, Texas. The therapeutics ow through nanochannels can be tightly controlled by several factors such as channels dimension, channel polarity, solution ionic strength just to name a few. The major advantage of this nanotechnology is that the drug ow results to be linear over time and practically independent on the concentration gradient between the molecules reservoir and the outer regions. Therefore, it is possible to develop a reliable, robust, drug delivery implant that does not rely on mechanical components. This implant was extensively tested both in vitro and in vivo condition, providing remarkable results that lead to several publications. The nanochannels, key compo- nent of the device, were fabricated using cutting edge photolithography techniques starting from a silicon wafer. The result is a highly compacted and mechanical robust silicon membrane containing more the 300,000 parallel, identical slit nanochan- nels. The diffusion ow through the membranes was studied with a wide range of nanochannels size ranging from 250 nm down to 2.5 nm. At the ultra-nanoscale (less than 10 nm) the molecules passage is highly affected by the electrostatic forces and close interaction forces, requiring a new and more accurate model to describe the phenomena, since the continuum hypothesis is no longer valid. This lead to two additional articles (yet to be published) concerning the ow of nitrogen gases and different drug molecules affected by the channel hindrance. Last portion of the presented thesis is centered on how electric elds across the nanochannel membrane can affect the passage of charged molecules. The results proved that, depending on the channel dimension and the ionic strength of the solution different phenomena can occur. With channels greater than the 100 nm in height it is possible to encounter behavior well described by electrophoretic or electroosmotic ows. On the other vii hand, in the ultra-nanoscale regime ionic concentration polarization is vastly predom- inant. However, regardless on the phenomena involved, it is possible to effectively control, thanks to the application of a strong electric eld (greater than 1kV/m), the ow of the charged therapeutics increasing, decreasing or even stopping the drug release. This lead to the development of a more advance implantable platform that can be remotely controlled via Bluetooth Low Energy. This new device will be able to continuously change the patient’s dosage depending on several factor such as time, patient’s sex, age, or health condition in that instant, granting access to true personalized therapies. Over the course of the pH.D., the technology was developed and tested for several therapeutics. Nano-electro uidics was successfully leveraged for the modulation drug such as Enalapril, Methotrexate, Penrindropil, Atenolol, Cezafolin and DF-1. The molecules were selected as a model analytes due to their valences, which render the molecules responsive to applied potentials, as well as their possible use as ther- apeutics to treat a broad range of diseases, including rheumatoid arthritis, several types of cancer, and hypertension. Release experiments were conducted in high ionic strength solutions to better simulate the in vivo environment. Experiments demon- strated that reproducible, active modulation could be achieved for clinically relevant molecules and sustained for long periods depending on the power consumption and battery capacity. This study evolved from a raw concept to a truly implantable device currently tested in vivo.