Randy Goodall

A robust nanofluidic membrane with tunable zero-order release for implantable dose specific drug delivery

This manuscript demonstrates a mechanically robust implantable nanofluidic membrane capable of tunable long-term zero-order release of therapeutic agents in ranges relevant for clinical applications. The membrane, with nanochannels as small as 5 nm, allows for the independent control of both dosage and mechanical strength through the integration of high-density short nanochannels parallel to the membrane surface with perpendicular micro- and macrochannels for interfacing with the ambient solutions. These nanofluidic membranes are created using precision silicon fabrication techniques on silicon-on-insulator substrates enabling exquisite control over the monodispersed nanochannel dimensions and surface roughness. Zero-order release of analytes is achieved by exploiting molecule to surface interactions which dominate diffusive transport when fluids are confined to the nanoscale. In this study we investigate the nanofluidic membrane performance using custom diffusion and gas testing apparatuses to quantify molecular release rate and process uniformity as well as mechanical strength using a gas based burst test. The kinetics of the constrained zero-order release is probed with molecules presenting a range of sizes, charge states, and structural conformations. Finally, an optimal ratio of the molecular hydrodynamic diameter to the nanochannel dimension is determined to assure zero-order release for each tested molecule.

Silicon Micro- and Nanofabrication for Medicine

This manuscript constitutes a review of several innovative biomedical technologies fabricated using the precision and accuracy of silicon micro- and nanofabrication. The technologies to be reviewed are subcutaneous nanochannel drug delivery implants for the continuous tunable zero-order release of therapeutics, multi-stage logic embedded vectors for the targeted systemic distribution of both therapeutic and imaging contrast agents, silicon and porous silicon nanowires for investigating cellular interactions and processes as well as for molecular and drug delivery applications, porous silicon (pSi) as inclusions into biocomposites for tissue engineering, especially as it applies to bone repair and regrowth, and porous silica chips for proteomic profiling. In the case of the biocomposites, the specifically designed pSi inclusions not only add to the structural robustness, but can also promote tissue and bone regrowth, fight infection, and reduce pain by releasing stimulating factors and other therapeutic agents stored within their porous network. The common material thread throughout all of these constructs, silicon and its associated dielectrics (silicon dioxide, silicon nitride, etc.), can be precisely and accurately machined using the same scalable micro- and nanofabrication protocols that are ubiquitous within the semiconductor industry. These techniques lend themselves to the high throughput production of exquisitely defined and monodispersed nanoscale features that should eliminate architectural randomness as a source of experimental variation thereby potentially leading to more rapid clinical translation.

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.

Analysis of a nanochanneled membrane structure through convective gas flow

Micro- and nano-fluidic devices are under development for a variety of applications including bio-molecular separation, drug delivery, biosensing and cell transplantation. Regulatory approval for the commercialization of these products requires the ability to fabricate a large number of these devices with high reproducibility and precision. Though traditional microscopy and particle rejection characterization techniques provide extremely useful measurements of nano-features, they are expensive and inadequate for quality control purposes. In this study, an agile and non-destructive selection method is presented which combines a predictive theoretical model with experimental analysis of convective nitrogen flow to detect structural defects in complex drug delivery membranes (nDS) combining both micro- and nanochanneled features. The mathematical model developed bridges the fluid dynamics between the micro- and nano-scales. An experimental analysis of gas flow was performed on a total of 250 membranes representing five different channel size configurations. The accuracy and reliability of this test in detecting major and minor defects of various kinds were verified by comparing the experimental results with the theoretical prediction.