Surgery – Diagnostic testing – Liquid collection
Reexamination Certificate
2000-03-10
2002-11-26
Hindenburg, Max (Department: 3736)
Surgery
Diagnostic testing
Liquid collection
C604S020000
Reexamination Certificate
active
06485437
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to a new and improved system for sampling and analysis of body fluids and the like, and may also include delivery of therapeutic agents in response to such analysis. More particularly, the invention relates to new and improved methods and apparatus for non-invasively withdrawing analytes from a biological subject automatically and controlling subsequent administration of therapeutic agents.
2. Description of the Related Art
Diagnosis for many human ills is dependent on evaluation of invasive samples of body fluids taken for assay. This invasive procedure is accomplished by withdrawal of the analyte or sample through a needle or the like, with consequent exposure of the patient to injury, possible infection and discomfort. The procedure invariably involves medical professionals that add to the cost of the procedure, e.g. an office visit.
Advances have recently been made in the biosensor field that enable diabetics, for instance, to self-test through the convenience of kits such as the ExacTech® device disclosed in U.S. Pat. Nos. 4,545,382 & 4,711,245. Such a device, while performing a valuable service and representing a quantum leap over professional intervention, is however, still invasive and subjects the patient to the same risks through multiple pin pricks and the like.
One approach to overcoming the aforementioned major shortcomings of invasive procedures is by noninvasive electro-osmotic analyte withdrawal through the unbroken skin or mucosal membrane. Electro-osmosis, sometimes referred to as cataphoresis and/or reverse iontophoresis, was recognized before 1941 by Nernst who showed that urea and sugar can be electrically transported out of the unbroken skin. An extensive bibliography exists on this basic phenomena.
A recent effort by Guy, et al., e.g. as described in U.S. Pat. Nos. 5,279,543 and 5,362,307, attempts to use this basic electro-osmosis technology to extract glucose. However, these attempts fall short of practical success because the proposed technology cannot perform the desired withdrawal procedure within a time span of less than ten minutes, as medically needed so that a glucose measurement would be followed in a timely manner after determination of the appropriate therapeutic insulin level. In this regard, continuously rapid changes of glucose levels, which commonly occurs, require different therapeutic insulin levels. Such limiting constraints on faster performance of sample withdrawal by the prior art is due to the restricted levels of current, voltage and time duration for the device to extract a sample and yet prevent skin injury. Accordingly, the prior art systems offer nothing new in basic electro-osmosis technology to prevent skin injury. Moreover, there is no subsequent controlled automatic delivery of an appropriate therapeutic agent in response to such rapid sample withdrawal and analysis.
Further difficulties have been encountered in achieving satisfactory dosimetry control for iontophoretic administration systems.
Hence, those concerned with the development and use of analyte withdrawal and evaluation systems have long recognized the need for very rapid, painless, accurate, non-invasive analyte withdrawal and analysis and subsequent controlled automatic delivery of therapeutic agents in response to such analysis. The present invention clearly fulfills all these needs.
SUMMARY OF THE INVENTION
Briefly, and in general terms, the present invention provides a new and improved system for sampling and analysis of body fluids, e.g., analytes, and delivery of therapeutic agents in response to such analysis and, more particularly, to improvements in methods and apparatus for non-invasively withdrawing and accurately evaluating analytes quickly, painlessly and reliably from a biological subject automatically and controlling subsequent administration of therapeutic agents in response to such analyte sample analysis.
By way of example, and not necessarily by way of limitation, the present invention provides a system wherein limits of low electrical voltage and current previously imposed on prior art systems to prevent skin injury, are now overcome through unique electrical circuitry and long tunnel physical routing of applied electrical voltage, thereby achieving high sampling current density. This facilitates rapid sampling which can be completed well under 10 minutes. In this regard, the process of the present invention enables use of 60 volts or more producing a controlled sampling current for complete comfort, and provides an analyte reading in 15 seconds or less.
In accordance with the invention, the aforedescribed features are accomplished, in part, by providing a long tortuous path between the applied high voltage and the skin of a biological subject. This path between the voltage source and the skin typically consists of a solvent or water wetted wool as an intervenor. Since the injury is caused by sodium hydroxide (lye) migrating from the negative voltage source electrode, the wool (or composite) acts as a barrier to the rather large sodium hydroxide molecule to prevent injury within the 10 minute treatment period.
Since one aspect of the invention involves a diagnostic tool, accuracy and repeatability are paramount. To achieve this, the invention provides that the current and time used to obtain the analyte sample be integrated and interdependent on each other, so that the identical quantitative sampling is always obtained. In this way, the identical amount of analyte is always withdrawn as a sample, despite the substantial variabilities of skin resistance on an individual.
Another aspect that limits the use of higher electrical currents is the pain involved. Usually, both electrical polarities are in direct contact with the skin through a felt or gel intervenor. Of the two polarities, the sensation at the positive electrode is typically far more painful. If therefore, direct contact of the positive electrode is removed from the skin, it allows a large increase in sampling current without the discomfort normally associated with such electrical currents and while still obtaining the analyte such as glucose at the negative electrode.
To eliminate pain caused by the positive polarity at high currents, additional novel technology is provided in accordance with the invention. Previously used circuitry in iontophoresis used both electrical polarities applied to the skin surface to “complete” or ground the circuit. In the practice of the present invention, the negative polarity is chosen to sample an analyte such as glucose and the positive electrode is no longer directly connected to the body as a ground return but stays within the device housing with its dropping resistor connected to the skin (ground) to complete the circuit. This ground is essentially neutral electrically. The negative polarity is in electrical contact with the skin through the aforedescribed wetted, long wool intervenor and then through a wetted membrane on the skin which acts as a collector for the analyte. Of course, for other applications these polarities could be reversed and, again, only a single electrical polarity is in contact with the skin.
The present invention also provides a system to assay or measure the sample. A pair of electrodes are provided facing each other with analyte selective enzyme coated on one electrode, e.g., the working electrode, or, alternatively, on the membrane facing the working electrode. A bi-layer membrane is inserted between these electrodes and serves the purpose of connecting directly to the skin on one end while the other end is in contact with the long narrow intervenor that is connected to the high voltage negative source. When wetted with an electrolyte of pH 7.4, a continuous circuit is provided from this high voltage source to the skin (with felt pad and membrane in between). Thus, in accordance with the invention, a “sandwiched” bi-layer membrane in between an enzyme coated electrode(s) or membrane is provided as a mechanical structure to extract th
Fulwider Patton Lee & Utecht LLP
Hindenburg Max
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