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.

Fiberoptic microneedle device facilitates volumetric infusate dispersion during convection-enhanced delivery in the brain.

BACKGROUND AND OBJECTIVES: A fiberoptic microneedle device (FMD) was designed and fabricated for the purpose of enhancing the volumetric dispersal of macromolecules delivered to the brain through convection-enhanced delivery (CED) by concurrent delivery of sub-lethal photothermal hyperthermia. This study's objective was to demonstrate enhanced dispersal of fluid tracer molecules through co-delivery of 1,064 nm laser energy in an in vivo rodent model. MATERIALS AND METHODS: FMDs capable of co-delivering fluids and laser energy through a single light-guiding capillary tube were fabricated. FMDs were stereotactically inserted symmetrically into both cerebral hemispheres of 16 anesthetized rats to a depth of 1.5 mm. Laser irradiation (1,064 nm) at 0 (control), 100, and 200 mW was administered concurrently with CED infusions of liposomal rhodamine (LR) or gadolinium-Evans blue-serum albumin conjugated complex (Gd-EBA) at a flow rate of 0.1 µl/min for 1 hour. Line pressures were monitored during the infusions. Rodents were sacrificed immediately following infusion and their brains were harvested, frozen, and serially cryosectioned for histopathologic and volumetric analyses. RESULTS: Analysis by ANOVA methods demonstrated that co-delivery enhanced volumetric dispersal significantly, with measured volumes of 15.8 ± 0.6 mm(3) for 100 mW compared to 10.0 ± 0.4 mm(3) for its fluid only control and 18.0 ± 0.3 mm(3) for 200 mW compared to 10.3 ± 0.7 mm(3) for its fluid only control. Brains treated with 200 mW co-delivery exhibited thermal lesions, while 100 mW co-deliveries were associated with preservation of brain cytoarchitecture. CONCLUSION: Both lethal and sub-lethal photothermal hyperthermia substantially increase the rate of volumetric dispersal in a 1 hour CED infusion. This suggests that the FMD co-delivery method could reduce infusion times and the number of catheter insertions into the brain during CED procedures.

Intracranial hyperthermia through local photothermal heating with a fiberoptic microneedle device.

BACKGROUND AND OBJECTIVES: The fiberoptic microneedle device (FMD) seeks to leverage advantages of both laser-induced thermal therapy (LITT) and convection-enhanced delivery (CED) to increase volumetric dispersal of locally infused chemotherapeutics through sub-lethal photothermal heat generation. This study focused on determination of photothermal damage thresholds with 1,064 nm light delivered through the FMD into in vivo rat models. MATERIALS AND METHODS: FMDs capable of co-delivering laser energy and fluid agents were fabricated through a novel off-center splicing technique involving fusion of a multimode fiberoptic to light-guiding capillary tubing. FMDs were positioned at a depth of 2.5 mm within the cerebrum of male rats with fluoroptic temperature probes placed within 1 mm of the FMD tip. Irradiation (without fluid infusion) was conducted at laser powers of 0 (sham), 100, 200, 500, or 750 mW. Evans blue-serum albumin conjugated complex solution (EBA) and laser energy co-delivery were performed in a second set of preliminary experiments. RESULTS: Maximum, steady-state temperatures of 38.7 ± 1.6 and 42.0 ± 0.9 °C were measured for the 100 and 200 mW experimental groups, respectively. Histological investigation demonstrated needle insertion damage alone for sham and 100 mW irradiations. Photothermal damage was detected at 200 mW, although observable thermal damage was limited to a small penumbra of cerebral cortical microcavitation and necrosis that immediately surrounded the region of FMD insertion. Co-delivery of EBA and laser energy presented increased volumetric dispersal relative to infusion-only controls. CONCLUSION: Fluoroptic temperature sensing and histopathological assessments demonstrated that a laser power of 100 mW results in sub-lethal brain hyperthermia, and the optimum, sub-lethal target energy range is likely 100-200 mW. The preliminary FMD-CED experiments confirmed the feasibility of augmenting fluid dispersal using slight photothermal heat generation, demonstrating the FMD's potential as a way to increase the efficacy of CED in treating MG.

Spatially controlled photothermal heating of bladder tissue through single-walled carbon nanohorns delivered with a fiberoptic microneedle device.

Laser-based photothermal therapies for urothelial cell carcinoma (UCC) are limited to thermal ablation of superficial tumors, as treatment of invasive lesions is hampered by shallow light penetration in bladder tissue at commonly used therapeutic wavelengths. This study evaluates the utilization of sharp, silica, fiberoptic microneedle devices (FMDs) to deliver single-walled carbon nanohorns (SWNHs) serving as exogenous chromophores in conjunction with a 1,064-nm laser to amplify thermal treatment doses in a spatially controlled manner. Experiments were conducted to determine the lateral and depth dispersal of SWNHs in aqueous solution (0.05 mg/mL) infused through FMDs into the wall of healthy, inflated, ex vivo porcine bladders. SWNH-perfused bladder regions were irradiated with a free-space, CW, 1,064-nm laser in order to determine the SWNH efficacy as exogenous chromophores within the organ. SWNHs infused at a rate of 50 µL/min resulted in an average lateral expansion rate of 0.36 ± 0.08 cm(2)/min. Infused SWNHs dispersal depth was limited to the urothelium and muscular propria for 50 µL/min infusions of 10 min or less, but dispersed through the entire thickness after a 15-min infusion period. Irradiation of SWNH-perfused bladder tissue with 1,064 nm laser light at 0.95 W/cm(2) over 40 s exhibited a maximum increase of approximately 19 °C compared with an increase of approximately 3 °C in a non-perfused control. The results indicate that these silica FMDs can successfully penetrate into the bladder wall to rapidly distribute SWNHs with some degree of lateral and depth control and that SWNHs may be a viable exogenous chromophore for photothermal amplification of laser-based UCC treatments.