Eric E. Nuxoll

Hard and soft micro- and nanofabrication: An integrated approach to hydrogel-based biosensing and drug delivery

We review efforts to produce microfabricated glucose sensors and closed-loop insulin delivery systems. These devices function due to the swelling and shrinking of glucose-sensitive microgels that are incorporated into silicon-based microdevices. The glucose response of the hydrogel is due to incorporated phenylboronic acid (PBA) side chains. It is shown that in the presence of glucose, these polymers alter their swelling properties, either by ionization or by formation of glucose-mediated reversible crosslinks. Swelling pressures impinge on microdevice structures, leading either to a change in resonant frequency of a microcircuit, or valving action. Potential areas for future development and improvement are described. Finally, an asymmetric nano-microporous membrane, which may be integrated with the glucose-sensitive devices, is described. This membrane, formed using photolithography and block polymer assembly techniques, can be functionalized to enhance its biocompatibility and solute size selectivity. The work described here features the interplay of design considerations at the supramolecular, nano, and micro scales.

Composite Block Polymer−Microfabricated Silicon Nanoporous Membrane

Block polymers offer an attractive route to densely packed, monodisperse nanoscale pores. However, their fragility as thin films complicates their use as membranes. By integrating a block polymer film with a thin (100 microm) silicon substrate, we have developed a composite membrane providing both nanoscale size exclusion and fast transport of small molecules. Here we describe the fabrication of this membrane, evaluate its mechanical integrity, and demonstrate its transport properties for model solutes of large and small molecular weight. The ability to block large molecules without hindering smaller ones, coupled with the potential for surface modification of the polymer and the microelectromechanical system style of support, makes this composite membrane an attractive candidate for interfacing implantable sensing and drug-delivery devices with biological hosts.

BioMEMS devices for drug delivery

Successful therapeutic outcomes following the administration of drugs, including small molecules and large biomolecules, require not only the selection of a proper drug but also its delivery to the proper site of action, with proper temporal presentation. Drug delivery is an extremely broad area of research, as each molecule presents its own absorption, distribution, metabolism, excretion, and toxicology (ADMET) profile. Moreover, timing of drug release may affect the efficacy of a pharmacologic agent. Any means by which drug delivery can be actuated and controlled is, therefore, of interest, and there should be no surprise that microelectromechanical systems (MEMS) have received considerable attention over the past decade in the drug delivery field. The ability to generate two-dimensional (2-D) and three-dimensional (3-D) material constructs accurately and reproducibly using MEMS may lead to substantial advances over conventional drug delivery systems.

Hydrogel-based microsensors for wireless chemical monitoring.

We report fabrication and characterization of a new hydrogel-based microsensor for wireless chemical monitoring. The basic device structure is a high-sensitivity capacitive pressure sensor coupled to a stimuli-sensitive hydrogel that is confined between a stiff porous membrane and a thin glass diaphragm. As small molecules pass through the porous membrane, the hydrogel swells and deflects the diaphragm which is also the movable plate of the variable capacitor in an LC resonator. The resulting change in resonant frequency can be remotely detected by the phase-dip technique. Prior to hydrogel loading, the sensitivity of the pressure sensor to applied air pressure was measured to be 222kHz/kPa over the range of 41.9–51.1MHz. With a pH-sensitive hydrogel, the sensor displayed a sensitivity of 1.16MHz/pH for pH3.0–6.5, and a response time of 45 minutes.

Thermal mitigation of Pseudomonas aeruginosa biofilms

Bacterial biofilms infect 2–4% of medical devices upon implantation, resulting in multiple surgeries and increased recovery time due to the very great increase in antibiotic resistance in the biofilm phenotype. This work investigates the feasibility of thermal mitigation of biofilms at physiologically accessible temperatures. Pseudomonas aeruginosa biofilms were cultured to high bacterial density (1.7 × 109 CFU cm−2) and subjected to thermal shocks ranging from 50°C to 80°C for durations of 1–30 min. The decrease in viable bacteria was closely correlated with an Arrhenius temperature dependence and Weibull-style time dependence, demonstrating up to six orders of magnitude reduction in bacterial load. The bacterial load for films with more conventional initial bacterial densities dropped below quantifiable levels, indicating thermal mitigation as a viable approach to biofilm control.

Magnetic nanoparticle/polymer composites for medical implant infection control

New potential medical applications for magnetic nanoparticle/polymer composite coatings, including deactivation of bacterial biofilms, require much higher power densities than can be supplied by previously developed polymer composites. These coatings in turn require much higher nanoparticle concentrations, where particle-particle and particle-polymer interactions play a significant role in the materials performance. This paper investigates the effect of several key design parameters on the resulting specific absorption rate of magnetite nanoparticle composites. Hydrophobic (poly(styrene), (PS)) and hydrophilic (poly(vinyl alcohol), (PVA)) polymer composite coatings were compared in both aqueous and non-aqueous solvents at multiple nanoparticle loadings and film thicknesses. Heating rates up to 717 W g-1 Fe were observed in a typical (2.32 kA m-1, 302 kHz) alternating magnetic field (AMF), achieving heating power densities up to 7.5 W cm-2. To estimate in vivo power requirements, electrical resistance heating beneath a tissue mimic heat sink indicated a peak power requirement of only 4.5 W cm-2 to achieve an 80 °C surface temperature in 15 s, demonstrating that these composites can exceed the power densities needed for applications such as treating bacterial infections on medical implants in situ. Polymer identity, solvent identity, and especially orientation within the magnetic field were shown to strongly affect the power density with effects that are interrelated.

Top-down and bottom-up fabrication techniques for hydrogel based sensing and hormone delivery microdevices

We review a set of studies dealing with molecular (glucose) sensing and hormone delivery, in which the swelling and shrinking of a hydrogel as a function of glucose concentration play a central role. Confining hydrogels in microfabricated structures permits transduction of their chemomechanical behaviors. Prototype microdevices for wireless glucose sensing and closed loop insulin delivery control have been designed using hydrogels containing phenylboronic acid sidechains. While these devices exhibit desired responses, improved response time is needed, warranting further miniaturization. In a separate application, geometric confinement of glucose oxidase by a pH-sensitive hydrogel membrane sets up a nonlinear feedback loop which enables rhythmic swell/shrink cycles when the system is exposed to a constant glucose concentration. The latter system may be applied to delivery of gonadotropin release hormone, for which rhythmicity of secretion is essential for therapeutic function.

Poly(vinyl alcohol) tissue phantoms as a robust in vitro model for heat transfer

ABSTRACT Glutaraldehyde-crosslinked poly(vinyl alcohol) (PVA) was used to create pourable, volume-stable hydrogel tissue phantoms that demonstrate several advantages over traditional poly(acrylamide) phantoms. The crosslinker concentration, curing time, and curing temperature were tuned to produce a tissue phantom whose volume varied by <0.2% over a 25-day span. The thermal conductivity of the PVA phantoms was tuned across the physiological range from 0.475 to 0.795 W m−1°C−1 by incorporating inert particle fillers. Experimental thermal diffusivity trials demonstrated the method’s utility for creating reliable, versatile tissue phantoms for the in vitro study of heat transfer in biologically relevant scenarios. GRAPHICAL ABSTRACT

A Polymer Membrane Containing Fe0 as a Contaminant Barrier

A poly(vinyl alcohol) (PVA) membrane containing iron (Fe(0)) particles was developed and tested as a model barrier for contaminant containment. Carbon tetrachloride, copper (Cu2+), nitrobenzene, 4-nitroacetophenone, and chromate (Cr04(2-)) were selected as model contaminants. Compared with a pure PVA membrane, the Fe(0)/PVA membrane can increase the breakthrough lag time for Cu2+ and carbon tetrachloride by more than 100-fold. The increase in the lag time was smaller for nitrobenzene and 4-nitroacetophenone, which stoichiometrically require more iron and for which the PVA membrane has a higher permeability. The effect of Fe(0) was even smaller for CrO4(2-) because of its slow reaction. Forty-five percent of the iron, based on the content in the dry membrane prior to hydration, was consumed by reaction with Cu2+ and 15% by reaction with carbon tetrachloride. Similarly, 25%, 17%, and 6% of the iron was consumed by nitrobenzene, 4-nitroacetophenone, and CrO4(2-), respectively. These percentages approximately double when the loss of iron during membrane hydration is considered. The permeability of the Fe(0)/PVA membrane after breakthrough was within a factor of 3 for that of pure PVA, consistent with theory. These results suggest that polymer membranes with embedded Fe(0) have potential as practical contaminant barriers.

Thermal shock susceptibility and regrowth of Pseudomonas aeruginosa biofilms

Abstract Biofilms on implanted medical devices cause thousands of patients each year to undergo multiple surgeries to remove and replace the implant, driving billions of dollars in increased health care costs due to the lack of viable treatment options for in situ biofilm eradication. Remotely activated localised heating is under investigation to mitigate these biofilms; however, little is known about the temperatures required to kill the biofilms. To better understand the required parameters this study investigated the thermal susceptibility of biofilms as a function of their fluidic and chemical environment during growth, as well as their propensity for regrowth following thermal shock. Pseudomonas aeruginosa biofilms were cultured in shaker plate fluidic conditions in four different growth media, then thermally shocked at various temperatures and exposure times. Biofilms were re-incubated to determine their regrowth potential following thermal shocks of various intensities. Results indicate that growth media has little impact on thermal susceptibility, while fluidic conditions strongly influence susceptibility to modest thermal shocks. This effect disappears, however, with increasingly aggressive shocks, reducing biofilm populations by up to 5 orders of magnitude. Regrowth studies indicate a critical post-shock bacterial loading (∼103 CFU/cm2) below which the biofilms were no longer viable, while biofilms above that loading slowly regrew to their previous population density.