Quality Control Method for a Micro-Nano-Channel Microfabricated Device

A variety of silicon-fabricated devices is used in medical applications such as drug and cell delivery, and DNA and protein separation and analysis. When a fluidic device inlet is connected to a compressed gas reservoir, and the outlet is at a lower pressure, a gas flow occurs through the membrane toward the outside. The method relies on the measurement of the gas pressure over the elapsed time inside the upstream and downstream environments. By knowing the volume of the upstream reservoir, the gas flow rate through the membrane over the pressure drop can be calculated. This quality control method consists of measuring the gas flow through a device and comparing the results with a standard curve, which can be obtained by testing standard devices. Standard devices can be selected through a variety of techniques, both destructive and nondestructive, such as SEM, AFM, and standard particle filtration

Nanochanneled Device and Related Methods

A capsule configured for in vivo refilling of a therapeutic agent. In certain embodiments, the capsule may contain methotrexate

The Influence of Surface Protein Adsorption on Gold Nanoparticle Intratumoral Distribution and Retention

Nanomedicines’ inability to penetrate throughout the entire volume of a tumor due to heterogeneous distribution within the tumor mass remains a crucial limiting factor for a vast range of theranostic applications, including image-guided radiation therapy. Despite many studies conducted on the topic having shown the efficacy and biocompatibility of colloidal gold nanoparticles (GNPs), the biological effects of GNPs in the tumor microenvironment, including the particle–protein interaction and the consequent impact on cellular pathways and contrast enhancement remain unclear. In this regard, further investigations on how GNP surface passivation affects X-ray attenuation as well as in vivo biodistribution will clarify several aspects still under discussion in the scientific community, which so far have limited the clinical translation of their cancer-related applications. We aim to evaluate the influence of protein surface adsorption on the GNP biodistribution in Lewis lung carcinoma (LLC) tumor-bearing mice using high-resolution computed tomography (CT) pre-clinical imaging. We hypothesize that, by controlling the adsorption of proteins on the GNP surface, we can influence the intratumoral distribution and retention of the particles. GNPs approximately 34 nm in diameter were synthesized with a surface plasmon peak at ~530 nm, surface passivated with bovine serum albumin (BSA) to reduce opsonization and improve colloidal stability, and characterized with standard methods. Modulation of BSA adsorption on the GNPs was observed by tuning the pH of the immobilization medium from acidic to alkaline, which we quantified using Langmuir isotherms. CT phantom imaging was used to determine X-ray attenuation as a function of GNP concentration and surface functionalization. The in vitro study for evaluating the uptake of GNPs by LLC cells highlighted a difference in the internalization depending on the surface functionalization. In both cases, macropinocytosis was the trafficking mechanism, but while endosomes with citrate-GNPs can be found in different stages of maturation, cells treated with BSA-GNPs presented larger vesicles up to 1 μm in diameter. The in vivo study was performed by injecting intratumorally, concentrating GNPs into LLC solid tumors grown on the right flank of 6-week-old female C57BL/6 mice. Ten days post-injection, follow-up assessments with CT imaging showed the distribution and retention of the particles in the tumor. CT attenuation quantification based on bioimaging analysis for each time point was conducted. In vivo results showed significant heterogeneity in the intratumoral biodistribution of GNPs dependent on surface passivation. BSA-GNPs perfused predominately along the tumor periphery with few depositions throughout the entire tumor volume. This response can be explained by the abnormal and heterogeneous vascular structure of the LLC tumor, suggesting perfusion rather than permeability as the limiting factor for tumor accumulation of the GNPs. Despite the perivascular cluster accumulation, the BSA-GNP distribution diverged from that obtained after unpassivated, citrate-GNP intratumoral injections. In conclusion, our investigations have shown that surface passivation of GNPs is able to influence the mechanism of cellular uptake in vitro and their in vivo intratumoral diffusion, highlighting the spatial heterogeneity of the solid tumor

COMPUTATIONAL MODELING OF INTRAOCULAR DRUG TRANSPORT

In this work we present computational model for intraocular drug transport using coupled convective-diffusive equations. Model can simulate drug transport using either injection or by state of the art implant devices. We are using Navier-Stokes equation for fluid flow in vitreous humor, and composite smeared finite element (CSFE) for convection in rest of the eye and also for diffusion within the whole model. CSFE takes into account blood vessel properties, such as hydraulic and diffusive components. User interface tool CAD for pre- and post- processing is constructed which enables generation of geometries for patient specific purposes. Computational model provides results in a form convenient for investigation of effects of the drugs on different diseases, such as diabetic macular edema, uveitis, etc. This computational platform has potentials to become a powerful tool for optimization of therapies and simulation of different drugs.Publishe

Wireless Power Transfer Closed-Loop Control for Low-Power Active Implantable Medical Devices

Near-field resonant inductive coupling is the most mature wireless power transfer (WPT) method for implantable medical devices. Common commercial WPT components are not optimized neither to deliver small amounts of power nor to work with other than small air gaps. In this paper, a closed-loop control is integrated with commercial off-the-shelf WPT components to efficiently recharge and power an implantable device for controlled active drug delivery. The system keeps the transmitted power stable and reliable, achieving a 26 % transfer efficiency with delivered power of tens of milliwatts, guaranteeing an autonomy of 5 days with a 4-hour recharge. Overheating is kept around the 2 °C safety limit

Hyaluronate-Thiol Passivation Enhances Gold Nanoparticle Peritumoral Distribution When Administered Intratumorally in Lung Cancer

Biofouling is the unwanted adsorption of cells, proteins, or intracellular and extracellular biomolecules that can spontaneously occur on the surface of metal nanocomplexes. It represents a major issue in bioinorganic chemistry because it leads to the creation of a protein corona, which can destabilize a colloidal solution and result in undesired macrophage-driven clearance, consequently causing failed delivery of a targeted drug cargo. Hyaluronic acid (HA) is a bioactive, natural mucopolysaccharide with excellent antifouling properties, arising from its hydrophilic and polyanionic characteristics in physiological environments which prevent opsonization. In this study, hyaluronate-thiol (HA-SH) (MW 10 kDa) was used to surface-passivate gold nanoparticles (GNPs) synthesized using a citrate reduction method. HA functionalized GNP complexes (HA-GNPs) were characterized using absorption spectroscopy, scanning electron microscopy, zeta potential, and dynamic light scattering. GNP cellular uptake and potential dose-dependent cytotoxic effects due to treatment were evaluated in vitro in HeLa cells using inductively coupled plasma—optical emission spectrometry (ICP-OES) and trypan blue and MTT assays. Further, we quantified the in vivo biodistribution of intratumorally injected HA functionalized GNPs in Lewis Lung carcinoma (LLC) solid tumors grown on the flank of C57BL/6 mice and compared localization and retention with nascent particles. Our results reveal that HA-GNPs show overall greater peritumoral distribution (** p < 0.005, 3 days post-intratumoral injection) than citrate-GNPs with reduced biodistribution in off-target organs. This property represents an advantageous step forward in localized delivery of metal nano-complexes to the infiltrative region of a tumor, which may improve the application of nanomedicine in the diagnosis and treatment of cancer

Nanochanneled Device and Related Methods

A nanochannel delivery device and method of manufacturing and use. The nanochannel delivery device comprises an inlet, an outlet, and a nanochannel. The nanochannel may be oriented parallel to the primary plane of the nanochannel delivery device. The inlet and outlet may be in direct fluid communication with the nanochannel

Effects of Surface Protein Adsorption on the Distribution and Retention of Intratumorally Administered Gold Nanoparticles

The heterogeneous distribution of delivery or treatment modalities within the tumor mass is a crucial limiting factor for a vast range of theranostic applications. Understanding the interactions between a nanomaterial and the tumor microenvironment will help to overcome challenges associated with tumor heterogeneity, as well as the clinical translation of nanotheranostic materials. This study aims to evaluate the influence of protein surface adsorption on gold nanoparticle (GNP) biodistribution using high-resolution computed tomography (CT) preclinical imaging in C57BL/6 mice harboring Lewis lung carcinoma (LLC) tumors. LLC provides a valuable model for study due to its highly heterogenous nature, which makes drug delivery to the tumor challenging. By controlling the adsorption of proteins on the GNP surface, we hypothesize that we can influence the intratumoral distribution pattern and particle retention. We performed an in vitro study to evaluate the uptake of GNPs by LLC cells and an in vivo study to assess and quantify the GNP biodistribution by injecting concentrated GNPs citrate-stabilized or passivated with bovine serum albumin (BSA) intratumorally into LLC solid tumors. Quantitative CT and inductively coupled plasma optical emission spectrometry (ICP-OES) results both confirm the presence of particles in the tumor 9 days post-injection (n = 8 mice/group). A significant difference is highlighted between citrate-GNP and BSA-GNP groups (** p < 0.005, Tukey’s multiple comparisons test), confirming that the protein corona of GNPs modifies intratumoral distribution and retention of the particles. In conclusion, our investigations show that the surface passivation of GNPs influences the mechanism of cellular uptake and intratumoral distribution in vivo, highlighting the spatial heterogeneity of the solid tumor

Microfabrication of a High-Throughput Nanochannel Delivery/Filtration System

A microfabrication process is proposed to produce a nanopore membrane for continuous passive drug release to maintain constant drug concentrations in the patient s blood throughout the delivery period. Based on silicon microfabrication technology, the dimensions of the nanochannel area, as well as microchannel area, can be precisely controlled, thus providing a steady, constant drug release rate within an extended time period. The multilayered nanochannel structures extend the limit of release rate range of a single-layer nanochannel system, and allow a wide range of pre-defined porosity to achieve any arbitrary drug release rate using any preferred nanochannel size. This membrane system could also be applied to molecular filtration or isolation. In this case, the nanochannel length can be reduced to the nanofabrication limit, i.e., 10s of nm. The nanochannel delivery system membrane is composed of a sandwich of a thin top layer, the horizontal nanochannels, and a thicker bottom wafer. The thin top layer houses an array of microchannels that offers the inlet port for diffusing molecules. It also works as a lid for the nanochannels by providing the channels a top surface. The nanochannels are fabricated by a sacrificial layer technique that obtains smooth surfaces and precisely controlled dimensions. The structure of this nanopore membrane is optimized to yield high mechanical strength and high throughput