Remotely controlled nanofluidic implantable platform for tunable drug delivery.

Chronic diseases such as hypertension and rheumatoid arthritis are persistent ailments that require personalized lifelong therapeutic management. However, the difficulty of adherence to strict dosing schedule compromises therapeutic efficacy and safety. Moreover, the conventional one-size-fits-all treatment approach is increasingly challenged due to the intricacies of inter- and intra-individual variabilities. While accelerated technological advances have led to sophisticated implantable drug delivery devices, flexibility in dosage and timing modulation to tailor precise treatment to individual needs remains an elusive goal. Here we describe the development of a subcutaneously implantable remote-controlled nanofluidic device capable of sustained drug release with adjustable dosing and timing. By leveraging a low intensity electric field to modify the concentration driven diffusion across a nanofluidic membrane, the rate of drug administration can be increased, decreased or stopped via Bluetooth remote command. We demonstrate in vitro the release modulation of enalapril and methotrexate, first-line therapeutics for treatment of hypertension and rheumatoid arthritis, respectively. Further, we show reliable remote communication and device biocompatibility via in vivo studies. Unlike a pulsatile release regimen typical of some conventional controlled delivery systems, our implant offers a continuous drug administration that avoids abrupt fluctuations, which could affect response and tolerability. Our system could set the foundation for an on-demand delivery platform technology for long term management of chronic diseases.

The nanochannel delivery system for constant testosterone replacement therapy.

INTRODUCTION: The goal of testosterone replacement is to provide long-term physiological supplementation at sufficient levels to mitigate the symptoms of hypogonadism. AIM: The objective of this work is to determine if the implantable nanochannel delivery system (nDS) can present an alternative delivery strategy for the long-term sustained and constant release of testosterone. METHODS: A formulation of common testosterone esters (F1) was developed to enable nanochannel delivery of the low water soluble hormone. In vivo evaluation of testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels by liquid chromatography/mass spectrometry and a multiplex assay, respectively, in castrated Sprague-Dawley rats implanted with nDS-F1 implants or polymeric pellets was performed over a 6-month period. The percent of testosterone concentrations observed that fell within the normal range of testosterone levels for each animal was calculated and used to compare the study groups. MAIN OUTCOME MEASURES: Sustain release of testosterone in vivo for over 6 months. RESULTS: The subcutaneous release of F1 from nDS implants exhibited sustained in vivo release kinetics and attained stable clinically relevant plasma testosterone levels. Plasma LH and FSH levels were significantly diminished in nDS-F1 implant-treated animals, confirming biological activity of the released testosterone. CONCLUSIONS: In conclusion, we demonstrate that nDS-F1 implants represents a novel approach for the treatment of male hypogonadism. Further studies will be performed in view of translating the technology to clinical use.

Impedance characterization, degradation, and in vitro biocompatibility for platinum electrodes on BioMEMS.

Fine control of molecular transport through microfluidic systems can be obtained by modulation of an applied electrical field across channels with the use of electrodes. In BioMEMS designed for biological fluids and in vivo applications, electrodes must be biocompatible, biorobust and stable. In this work, the analysis and characterization of platinum (Pt) electrodes integrated on silicon substrates for biomedical applications are presented. Electrodes were incorporated on the surface of silicon chips by adhesion of laminated Pt foils or deposited at 30°, 45° or 90° angle by e-beam or physical vapor (sputtering) methods. Electrical and physical properties of the electrodes were quantified and evaluated using electrical impedance spectroscopy and modelling of the electrode-electrolyte interfaces. Electrode degradation in saline solution at pH 7.4 was tested at room temperature and under accelerated conditions (90 °C), both in the presence and absence of an applied electrical potential. Degradation was quantified using atomic force microscopy (AFM) and inductively coupled plasma mass spectroscopy (ICP-MS). Biocompatibility was assessed by MTT proliferation assay with human dermal fibroblasts. Results demonstrated that the deposited electrodes were biocompatible with negligible material degradation and exhibited electrochemical behavior similar to Pt foils, especially for e-beam deposited electrodes. Finally, Pt electrodes e-beam deposited on silicon nanofabricated nanochannel membranes were evaluated for controlled drug delivery applications. By tuning a low applied electrical potential (<1.5 VDC) to the electrodes, temporal modulation of the dendritic fullerene 1 (DF-1) release from a source reservoir was successfully achieved as a proof of concept, highlighting the potential of deposited electrodes in biomedical applications.

Leveraging electrokinetics for the active control of dendritic fullerene-1 release across a nanochannel membrane.

General adoption of advanced treatment protocols such as chronotherapy will hinge on progress in drug delivery technologies that provide precise temporal control of therapeutic release. Such innovation is also crucial to future medicine approaches such as telemedicine. Here we present a nanofluidic membrane technology capable of achieving active and tunable control of molecular transport through nanofluidic channels. Control was achieved through application of an electric field between two platinum electrodes positioned on either surface of a 5.7 nm nanochannel membrane designed for zero-order drug delivery. Two electrode configurations were tested: laser-cut foils and electron beam deposited thin-films, configurations capable of operating at low voltage (≤1.5 V), and power (100 nW). Temporal, reproducible tuning and interruption of dendritic fullerene 1 (DF-1) transport was demonstrated over multi-day release experiments. Conductance tests showed limiting currents in the low applied potential range, implying ionic concentration polarization (ICP) at the interface between the membrane's micro- and nanochannels, even in concentrated solutions (≤1 M NaCl). The ability of this nanotechnology platform to facilitate controlled delivery of molecules and particles has broad applicability to next-generation therapeutics for numerous pathologies, including autoimmune diseases, circadian dysfunction, pain, and stress, among others.

Delivering enhanced testosterone replacement therapy through nanochannels.

Primary or secondary hypogonadism results in a range of signs and symptoms that compromise quality of life and requires life-long testosterone replacement therapy. In this study, an implantable nanochannel system is investigated as an alternative delivery strategy for the long-term sustained and constant release of testosterone. In vitro release tests are performed using a dissolution set up, with testosterone and testosterone:2-hydroxypropyl-ß-cyclodextrin (TES:HPCD) 1:1 and 1:2 molar ratio complexes release from the implantable nanochannel system and quantify by HPLC. 1:2 TES:HPCD complex stably achieve 10-15 times higher testosterone solubility with 25-30 times higher in vitro release. Bioactivity of delivered testosterone is verified by LNCaP/LUC cell luminescence. In vivo evaluation of testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) levels by liquid chromatography mass spectrometry (LC/MS) and multiplex assay is performed in castrated Sprague-Dawley rats over 30 d. Animals are treated with the nanochannel implants or degradable testosterone pellets. The 1:2 TES:HPCD nanochannel implant exhibits sustained and clinically relevant in vivo release kinetics and attains physiologically stable plasma levels of testosterone, LH, and FSH. In conclusion, it is demonstrated that by providing long-term steady release 1:2 TES:HPCD nanochannel implants may represent a major breakthrough for the treatment of male hypogonadism.

Sustained Administration of Hormones Exploiting Nanoconfined Diffusion through Nanochannel Membranes.

Implantable devices may provide a superior means for hormone delivery through maintaining serum levels within target therapeutic windows. Zero-order administration has been shown to reach an equilibrium with metabolic clearance, resulting in a constant serum concentration and bioavailability of released hormones. By exploiting surface-to-molecule interaction within nanochannel membranes, it is possible to achieve a long-term, constant diffusive release of agents from implantable reservoirs. In this study, we sought to demonstrate the controlled release of model hormones from a novel nanochannel system. We investigated the delivery of hormones through our nanochannel membrane over a period of 40 days. Levothyroxine, osteocalcin and testosterone were selected as representative hormones based on their different molecular properties and structures. The release mechanisms and transport behaviors of these hormones within 3, 5 and 40 nm channels were characterized. Results further supported the suitability of the nanochannels for sustained administration from implantable platforms.

Leveraging nanochannels for universal, zero-order drug delivery in vivo.

Drug delivery is essential to achieve effective therapy. Herein we report on the only implantable nanochannel membrane with geometrically defined channels as small as 2.5 nm that achieves constant drug delivery in vivo. Nanochannels passively control the release of molecules by physico-electrostatic confinement, thereby leading to constant drug diffusion. We utilize a novel design algorithm to select the optimal nanochannel size for each therapeutic agent. Using nanochannels as small as 3.6 and 20 nm, we achieve sustained and constant plasma levels of leuprolide, interferon α-2b, letrozole, Y-27632, octreotide, and human growth hormone, all delivered at clinically-relevant doses. The device was demonstrated in dogs, rats, and mice and was capable of sustaining target doses for up to 70 days. To provide evidence of therapeutic efficacy, we successfully combined nanochannel delivery with a RhoA pathway inhibitor to prevent chronic rejection of cardiac allografts in a rat model. Our results provide evidence that the nanochannel platform has the potential to dramatically improve long-term therapies for chronic conditions.