Constant-Volume Hydrogel Osmometer: A New Device Concept for Miniature Biosensors In Suk Han,* ,† Man-Hee Han, † Jinwon Kim, † Seok Lew, † Young Jun Lee, † Ferenc Horkay, ‡ and Jules J. Magda § M-Biotech Inc., 2411 South 1070 West, Suite C, Salt Lake City, Utah 84119; Section on Tissue Biophysics and Biomimetics, NICHD, National Institutes of Health, 13 South Drive, Bethesda, Maryland 20892-5772; and Department of Chemical & Fuels Engineering, 50 South Central Campus Drive, Room 3290, University of Utah, Salt Lake City, Utah 84112 Received June 7, 2002; Revised Manuscript Received August 2, 2002 A new type of biosensor is proposed that combines the recognition properties of “intelligent” hydrogels with the sensitivity and reliability of microfabricated pressure transducers. In the proposed device, analyte- induced changes in the osmotic swelling pressure of an environmentally responsive hydrogel are measured by confining it within a small implantable enclosure between a rigid semipermeable membrane and the diaphragm of a miniature pressure transducer. Proof-of-principle tests of this device were performed in vitro using pH-sensitive hydrogels, with osmotic deswelling data for the same hydrogels used as a benchmark for comparison. The swelling pressure of the hydrogel was accurately determined from osmotic deswelling measurements against reservoirs of known osmotic stress. Values of swelling pressure vs salt concentration measured with a preliminary version of the sensor agree well with osmotic deswelling results. Through modification of the hydrogel with various enzymes or pendant binding moieties, the sensor has the potential to detect a wide range of biological analytes with good specificity. Introduction Clark and Lyons pioneered the development of biosensors in 1962, using an amperometric technique in which an enzymatic reaction involving the analyte produced a current in an electrode. 1 Sensor development continues to be an extremely active research area, due to the immense practical value of sensors in fields ranging from health care to environmental monitoring to the agricultural and chemical industries. 2-5 For example, due to great medical need, there is a major effort underway to develop a painless and inexpensive glucose sensor for continuous monitoring of blood glucose levels in diabetic patients. 6 The goal of any sensor design is the accurate and quantitative determination of the concentration of an analyte by detecting physical and/ or chemical signals proportional to the analyte concentration. 5 The transducer may be electrochemical, piezoelectric, ther- moelectric, acoustic, or optical in nature, depending on the analyte property being measured. We present here proof-of- principle results for a novel approach that takes advantage of recent advances in microfabricated pressure transducers 7 and “intelligent” polymer hydrogels. 8 The basic principle of operation is sketched in Figure 1. Figure 1A shows a conventional approach for use of stimuli-responsiVe hydrogels. A stimulus-reponsive hydrogel is a cross-linked polymer network that changes its swelling ratio in response to some stimulus in the environment such as pH, temperature or concentration of a particular analyte. 9 A glucose-sensitiVe hydrogel changes its swelling ratio in response to the environmental glucose concentration. In one * To whom correspondence may be addressed. Telephone: (801) 975- 0747. Fax: (801) 975-0746. E-mail: m-biotech@m-biotech.com. † M-Biotech Inc. ‡ National Institutes of Health. § University of Utah. Figure 1. Schematic representation of new sensor approach: (A) swelling of unconfined responsive hydrogel; (B) responsive hydrogel at fixed volume in sensor between rigid porous membrane and diaphragm of miniature pressure transducer. 1271 Biomacromolecules 2002, 3, 1271-1275 10.1021/bm0255894 CCC: $22.00 © 2002 American Chemical Society Published on Web 09/04/2002