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Technical Program TRACK 6

Expanded Control of Ionic Diffusion Through Enhanced Na- be extended to several different systems for filtration, sorting, or desalina-
noscale Confinement tion, among others. The nanochannel drug delivery system (nDS) is an im-
plantable platform employing a silicon, nanochannel membrane and applied
Poster Presentation. NEMB2016-6025 electric fields for the active and remote modulation of therapeutic transport
from the inner reservoir to the outer environment. The nanochannels were
manufactured using industrial grade processes and etched in parallel to
R. Lyle Hood, Giacomo Bruno, Priya Jain, Alessandro Grattoni, achieve a highly dense array (over 100,000 nanochannels per mm2) while
Houston Methodist Research Institute, Houston, TX, United States maintaining sub-nanometer precision. This group has previously demonstrat-
ed the advantages of nanochannels in drug delivery by releasing different
Physiological hormone regulation in complex organisms is precisely con- types of therapeutics over long periods (6 months) both in vitro and in vivo.
trolled down to picomolar specificity. Emulation of these systems can be In nanofluidics, where molecules are confined into nano-spaces, the diffu-
accomplished through nanofluidic controlled delivery, which also offers po- sion redistribution results as the major transport phenomenon. This leads
tential solutions in many other applications, including drug delivery, desalina- to a zero-order flux of drugs through the membrane and into the patient,
tion, and filtration, among others. reducing potential side effects and enhancing the efficacy and efficiency of
the healing process. The next generation nDS leverages the use of a strong
Previously, this group has demonstrated controlled release with a broad electric field (greater than 1kV/m) to modulate the release of molecules from
set of drugs and biomolecules both in vitro and in vivo, leveraging trans- the implantable device. A small potential of 1.5 V was applied between two
port phenomena unique to the nanoscale regime into clinically useful drug platinum electrodes sputtered on the faces of the silicon membrane and
release. In this study, we present a set of experiments providing an unprec- controlled via Bluetooth by a microprocessor incorporated within the nDS.
edented characterization of nanofluidic diffusion with a model cation (hista- Depending on the size of the nanochannels, different phenomena occurred
mine) and anion (cefazolin) through nanochannels. Achieving sub-nanometer when a electrical potential was present. For large nanochannels (greater
resolution and reliability in silicon membranes, we were able to observe than 20 nm) the electro-kinetic transport regulated the therapeutic flux de-
several diffusion-driven regimes dependent on the ratio between the nano- pending on the polarity of the potential applied. Au contraire, smaller nano-
channels’ height and ions’ hydrodynamic radii. channels exhibit a phenomenon termed Ionic Concentration Polarization
(ICP), which resulted in a complete stop of drug passage. To investigate this
The diffusive release of histamine (111 Da, +2e at pH 3.54) and cefazolin (455 further, a thorough evaluation of ICP though a wide range of nanochannels
Da, -1e at pH 7.61) were examined through a scaled series of nanochannel was conducted. Experiments employed channels 2.5, 3.6, 5.7, 13, 20, 40,
membranes with distinct sizes: 2.5, 3.6, 5.7, 13, 20, 40, and 200 nm in height. 200 nm in height and different ionic concentrations ranging from 100 µMol
Release experiments were quantified through UV-Vis spectroscopy and to 1 Mol NaCl. The results highlighted three separate regions: ICP did not
conducted with the ions solubilized in aqueous 10 mM NaCl solutions and occur, ICP limited the transport velocity, or ICP blocked the ionic flux, which
at the pH stated above over 24-48 hours. Size scaling, exponential bulk allowed decoupling of the phenomenon involved. The novel properties of
diffusion was observed as the major transport phenomenon for both ions the next generation nDS allows active and external control of drug transport,
within the largest nanochannels (200 nm). In the intermediate range (5.7-40 provides tuning of the therapeutic administration over time, and motivates
nm), histamine demonstrated near-surface diffusion behavior speculated future medicine possibilities such as personalized and telemedicine treat-
to arise from positively charged ions diffusing along the negative silicon ment protocols. The capability of this nanotechnology platform to temporally
surfaces (2D dominated transport). This was evidenced by overall transport control the diffusive release of molecules offers potential solutions in man-
rates remaining nearly identical regardless of channel size and following an agement of several chronic diseases such as cancer, heart disease, circadi-
exponential profile. Cefazolin demonstrated substantially different transport an dysfunction, hypertension, pain, and stress, as well as directly enabling
in the 5.7-40 nm channels, as release rates correlated linearly with channel modern treatment regimens such as chronotherapy.
size and maintained a zero-order profile. This is attributed to repulsion from
the negative channel surfaces restricting ionic diffusion to the center of the
channel (gated diffusion, 3D dominated transport).
Nanochannel Membranes for Sustained HIV Prophylaxis
However, transport within the finest nanochannels (2.5 and 3.6 nm) exhibited
previously unobserved charge independent behaviors. For both ions, the Poster Presentation. NEMB2016-6032
release rate dropped by 1-2 orders of magnitude, a particularly marked de-
cline for histamine following the identical rates for the 5.7-40 nm channels. In Priya Jain, R. Lyle Hood, Eugenia Nicolov, Houston Methodist Re-
this domain, sustained zero-order release profiles scaling with nanochannel search Institute, Houston, TX, United States, Roberto Arduino, The
height were observed for both ions. A noteworthy finding was the linear- University of Texas Health Science Center at Houston, Houston, TX,
ization of small cation transport (histamine), which, to our knowledge, is an United States, Alessandro Grattoni, Houston Methodist Research
original demonstration. This study highlights the relevance of nanofluidic Institute, Houston, TX, United States
systems as tools for investigating novel transport phenomena and demon-
strates the potential for controlled, zero-order delivery of clinically relevant
Introduction:
ions regardless of their expressed charge, overcoming a primary limitation
of the approach. The Human Immunodeficiency Virus (HIV) affects over 35 million people
globally with 2 million new infections arising in 2014. Truvada, a combination
of tenofovir and emtricitabine, has been demonstrated to be an effective
drug for HIV prevention; however, adherence to this once-a-day regimen
Tunable Control of Therapeutics Release through Electric Field has been shown to be of primary clinical concern. Our BioMEMS nanoflu-
Modulated Transport in Nanochannels idic nanochannel Delivery System (nDS) introduces a method to overcome
this adherence issue by developing an implantable device that provides
Poster Presentation. NEMB2016-6029 constant, long-term delivery. This system employs a silicon membrane
containing more than 100,000/cm2 nanochannels that can be varied in size
Giacomo Bruno, Thomas Geninatti, R. Lyle Hood, houston meth- from 2.5-250 nm to adapt for the drug of interest and desired dosage rate.
odist research institute, houston, TX, United States, Giovanni Scor- Developing a novel approach to refill the device transcutaneously provides
a minimally-invasive method to release drugs over a period of years instead
rano, Rice university, Houston, TX, United States, Alessandro Grat- of months.
toni, Houston Methodist Research Institute, Houston, TX, United
States, Danilo Demarchi, Politecnico di Torino, Turin, Italy Materials and Methods:
80 Emtricitabine (FTC) and tenofovir alafenamide (TAF) were kindly provided by
Nanofluidic devices have been investigated for over a decade as promising Gilead Sciences to test with our implantable nDS. In vitro experiments were
platforms for the controlled release of therapeutics, but their potential can performed using nanochannel membranes mounted within PEEK capsules