Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving glucose or galactose
Reexamination Certificate
2002-04-11
2004-12-28
Redding, David A (Department: 1744)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving glucose or galactose
C435S025000, C435S288700, C359S290000, C436S095000, C436S148000
Reexamination Certificate
active
06835553
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
This invention relates generally to biosensors for measuring physiological analytes in humans, and particularly to biosensors suitable for implantation to provide in vivo monitoring of a selected analyte, such as monitoring of blood glucose levels in diabetics.
2. Description of Related Art
For some time the medical community has recognized a need for implantable biosensors to monitor physiologically important analytes. The need is particularly pressing for continuous monitoring of blood glucose in diabetics, since failure to properly maintain glucose levels leads to serious consequences in both the short and long term. The long-term consequences include kidney failure, blindness, and amputation. To date, however, the only test readily available is a fingerstick kit, which does not provide continuous monitoring. Most diabetics use such kits infrequently at best, because of the pain and inconvenience associated with them.
In developing various implantable devices, hydrogels have been widely used as protective biocompatible coatings for the devices. Hydrogels are generally defined as polymeric materials that swell in water and other fluids, absorbing the fluid within the polymer network without dissolving. Hydrophilic hydrogels have a large amount of water content at equilibrium, and good biocompatibility.
The above-described properties of hydrogels make them attractive for use in implantable biosensors. One such device is an implantable amperometric sensor intended to measure glucose levels in blood or body fluids (U.S. Pat. No. 4,703,756 to Gough et al.). A second type of hydrogel biosensor which uses a pressure transducer to measure changes in osmotic pressure in pH-sensitive hydrogels, developed by the present inventors, is described in U.S. Pat. No. 6,268,161 to Han et al., and in co-pending U.S. patent application Ser. Nos. 09/308,392 and 09/644,323.
The Gough et al. biosensor uses the enzymatic activity of glucose oxidase (GOX) to measure glucose levels. GOX catalyzes the conversion of glucose to gluconic acid and hydrogen peroxide (H
2
O
2
), consuming oxygen in the process. The GOX reaction can be followed using electrochemical transducers of various kinds, but the most advanced type of device is the amperometric sensor. In the amperometric method, an electrode produces a current proportional to the diffusional flux of hydrogen peroxide to the electrode surface, or, alternatively, proportional to the diffusional flux of oxygen (O
2
) to the electrode surface. An increase in the surrounding glucose concentration should increase the diffusional flux of glucose into the membrane and increase the reaction rate within the membrane. The increase in enzymatic reaction rate in turn should increase the local hydrogen peroxide concentration and decrease the local oxygen concentration within the membrane. This increases the current detected by a hydrogen peroxide-based electrode sensor, or decreases the current to an oxygen-based electrode sensor. The latter approach, based on detecting the oxygen flux, requires a reference oxygen-based electrode sensor located in a hydrogel without the enzyme.
A second class of osmotic-pressure hydrogel sensors uses a pressure transducer to directly measure osmotic pressure changes in a hydrogel disposed within a rigid chamber having one open side which is covered with a flexible, semi-permeable diaphragm (Han et al., U.S. Pat. No. 6,268,161; Han et al., U.S. application Ser. Nos. 09/839,993 and 09/644,323). The pressure transducer senses changes in the pressure exerted by the hydrogel on the flexible diaphragm. Two types of such sensors have been developed. One uses pH-sensitive hydrogels having immobilized GOX. In this device, the gluconic acid produced by enzymatic action of GOX on free glucose changes the pH in the fluid matrix, causing it to swell (if the hydrogel has pendant acidic groups) or to shrink (if the hydrogel has pendant basic groups). The second type, which has potentially far wider application, uses the principles of the competitive binding assay. Both analyte and analyte-binding molecules are immobilized within the hydrogel; noncovalent bonds between the two effectively produce crosslinks. When free analyte displaces immobilized analyte, the crosslinking index changes, producing either swelling or shrinking of the hydrogel (depending on other factors in hydrogel composition). The resulting changes in osmotic pressure are measured with a pressure transducer in the same way as for the GOX osmotic-pressure biosensor. Where the analyte is glucose, the immobilized analyte binding molecule may for example be concanavalin A.
In addition to the above-described biosensors, there is another hydrogel-based glucose measurement system that measures the displacement change of the hydrogel in the pending U.S. Provisional Patent Application Ser. No. 60/316731 to Lew et al. and in co-pending U.S. patent application Ser. No. 10/054660. The swelling displacement of the implanted hydrogel is monitored by image capture from outside the body such as an ultrasound scanning device, and the change of displacement characterizes the glucose concentration.
SUMMARY OF THE INVENTION
The present invention comprises a hydrogel-based biosensor that measures the displacement of an analyte-sensitive hydrogel filament such as glucose-sensitive hydrogel filament (GSF). In order to measure the displacement, the hydrogel filament is placed in a rigid column that has at least one semi-permeable opening to permit contact between the hydrogel filament and the test fluid (a patient's blood or other solution), and a photometric displacement detection means is provided for detecting the displacement of the hydrogel filament.
Two types of specially chemically configured hydrogels are presently preferred for use in the invention. In one, an oxidative enzyme is immobilized within a pH-sensitive hydrogel, and catalyzes a reaction of the analyte to produce a charged product. The term ‘pH-sensitive hydrogel’ refers generally to a hydrogel modified to contain pendant charged groups in proportions that produce an overall acidic or basic environment in the fluid within the gel. The immobilized enzyme might be, for example, glucose oxidase, GOX, where the analyte to be measured is glucose. The charged product generated by activity of the enzyme on the analyte causes the hydrogel to change its displacement volume (swell or shrink), which changes can be detected by the displacement detection means. The second type of hydrogel has both analyte binding molecules (ABMs) and analyte or analyte analogue molecules (AAMs) co-immobilized within it, in addition to charged pendant groups. In the absence of free analyte, immobilized ABMs bind to immobilized AAMs, forming what are in effect non-covalent ‘crosslinks’. As free analyte from a body fluid or test solution diffuses into the hydrogel, binding competition displaces immobilized AAMs from ABMs, thus reducing the number of ‘crosslinks’. This reduction in crosslinking causes swelling of the hydrogel.
Also, in addition to the above two types of hydrogels, it is within contemplation that other analyte-sensitive swellable materials, polymers, and hydrogels meeting that description may be developed and will be useful in the biosensor. Certain embodiments of the invention are specifically designed to detect glucose levels in body fluids.
In its broadest conception, the invention is an implantable analyte (for example, glucose) biosensor containing an analyte-sensitive hydrogel filament and a photometric displacement transducer. The displacement of the hydrogel filament changes with changes in the concentration of the analyte. A set of a light source and light intensity detector (photoreceptor) measures the displacement of the hydrogel by detecting changes of intensity of light that falls on the detector: the intensity of light received is converted to an electric signal. In a preferred embodiment, a photo diode and a phototransistor are the light source and the light intensity detector, res
Han In Suk
Han Man Hee
Lew Seok
M-Biotech, Inc.
Mallinckrodt Robert R.
Mallinckrodt & Mallinckrodt
Redding David A
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