Integrating Biosensors and Drug Delivery: A Step Closer Toward Scalable Responsive Drug-Delivery Systems

2009 WILEY-VCH Verlag Gm The need for responsive individualized therapy has been a longheld but largely unattainable goal. An effective approach to individualized therapy involves the sensing of a marker molecule indicative of a disease, along with the subsequent delivery of a drug. An ideal microfabricated implantable drug-delivery device should integrate sensors and storage, and release components into a self-regulating ‘‘smart’’ device that could perform with minimal intervention. This is a challenging task, and can only be accomplished if each component is prepared individually and optimized before integration. Herein, we employed hybrid technologies to create an inexpensive, customizable, scalable drug-delivery platform that can be utilized for various medication types and dosages. As a model system, we demonstrate the integration of a biosensor for glucose employing glucose oxidase immobilized on a hydrogel contained within microfabricated vials of a device, which, in addition, contains a drug-delivery reservoir large enough (microliter volumes) to dispense therapeutic levels of protein biopharmaceuticals, such as insulin. For that, we developed polymer/gold microvalves, which can be reused and are suitable for both sensing and delivery. The sensing element is stored in the microvial to be protected from continuous exposure to harsh environments (e.g., the human body), and, when desired, the lid of the valve can be opened, and the microsensor exposed to the stream of the marker/analyte. Once sampling and/or detection of the target marker is accomplished, the lid is closed again. The valve can then be re-opened when an additional measurement is needed. In the drug-delivery application, the valve is open when a dose is required, and closed again after the desired amount is deployed. The molded polydimethylsiloxane (PDMS) drug reservoir allows for storage of different volumes of drug (from sub-microliter to microliter). The convergence of advanced microfabrication technologies and biological sciences has resulted in the design and fabrication of new types of microscale devices – biological micro-electromechanical systems (BioMEMS) – that can be employed in a wide variety of applications. Responsive drug-delivery systems, a type of BioMEMS, integrate biosensors capable of monitoring the levels of physiological parameters of a patient and, in response, trigger the release of drugs on a need-basis, to customize drug administration and minimize harmful side effects. The prototype drug-delivery device reported herein consists of two parts: a molded PDMS drug/biosensor reservoir and a silicon substrate containing a drug-release valve. State-ofthe-art microfabricated drug-delivery devices can typically hold only nanoliter to sub-microliter volumes of drug, which limits the number of dosages of the device, especially when employing biopharmaceuticals that have a large specific mass and, thus, require a larger volume. In order to increase the size of the drug reservoir, a molded PDMS cap was sealed to the underlying silicon substrate. In this manner, an array of actuated valves can be manufactured and controlled individually. If multiple valves are covered by the same reservoir cap, opening a specified number of valves at the same time can control the rate of the drug release. Multiple reservoirs can also be positioned on the same substrate, to delivermedication in sequence at various times, or to deliver different kinds of medication. Two modalities – single reservoirs with multiple drug-release valves and multiple reservoirs (Fig. 1) – can be constructed using the same microfabricated substrate with drug-release valves. This substrate can also be used with reservoir cups of different sizes, required for various drug doses. Our scalable drug-delivery system can be manufactured in two parts – universal substrate with individuallycontrolled drug-release valves and a set of premolded drugreservoir cups. Based on each specific need, an appropriate size of the drug reservoir(s) can be chosen. Another advantage of the externally-sealed reservoir for an implantable system is that it creates a protected cavity, inside which a drug-release valve can be opened reliably without danger of being obstructed by tissue or nonspecifically adsorbed proteins, thus increasing the lifetime of the device. The drug-delivery device (Fig. 2) is fabricated by sequential deposition of chromium and gold layers. To enable operation of the microfabricated flap microvalve/actuator, the principle of ‘‘differential adhesion’’ is used. A chromium layer positioned between the gold and the silicon dioxide promotes adhesion of the stationary part of the actuated valve (anchor) to the substrate. The polyimide layer deposited under a movable part of the actuator (flap) is designed to inhibit adhesion of the flap to the underlying substrate. A hinge of the actuated flap valve is located at the point where the chromium layer ends. A polypyrrole (PPy) layer 3mm