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.

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.

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.

A polymer membrane containing Fe(0) 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.