Surgery – Diagnostic testing – Measuring or detecting nonradioactive constituent of body...
Reexamination Certificate
1999-06-30
2001-05-29
Winakur, Eric F. (Department: 3736)
Surgery
Diagnostic testing
Measuring or detecting nonradioactive constituent of body...
C600S310000, C250S341600
Reexamination Certificate
active
06240306
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to a non-invasive method and apparatus for measuring a blood analyte, particularly glucose, utilizing spectroscopic methods. More particularly, the method and apparatus incorporate means for equilibrating the concentration of specific analytes between tissue fluid compartments in a sample area, especially between blood and other tissue. The method and apparatus also includes an improved input optical interface for irradiating biological tissue with infrared energy having at least several wavelengths and an improved output optical interface for receiving non-absorbed infrared energy as a measure of differential absorption by the biological sample to determine an analyte concentration.
BACKGROUND OF THE INVENTION
The need and demand for an accurate, non-invasive method for determining blood glucose level in patients is well documented. Barnes et al. (U.S. Pat. No. 5,379,764) disclose the necessity for diabetics to frequently monitor glucose levels in their blood. It is further recognized that the more frequent the analysis, the less likely there will be large swings in glucose levels. These large swings are associated with the symptoms and complications of the disease, whose long-term effects can include heart disease, arteriosclerosis, blindness, stroke, hypertension, kidney failure, and premature death. As described below, several systems have been proposed for the non-invasive measurement of glucose in blood. However, despite these efforts a lancet cut into the finger is still necessary for all presently commercially available forms of home glucose monitoring. This is believed so compromising to the diabetic patient that the most effective use of any form of diabetic management is rarely achieved.
The various proposed non-invasive methods for determining blood glucose level, discussed individually below, generally utilize quantitative infrared spectroscopy as a theoretical basis for analysis. Infrared spectroscopy measures the electromagnetic radiation (0.7-25 &mgr;m) a substance absorbs at various wavelengths. Molecules do not maintain fixed positions with respect to each other, but vibrate back and forth about an average distance. Absorption of light at the appropriate energy causes the molecules to become excited to a higher vibration level. The excitation of the molecules to an excited state occurs only at certain discrete energy levels, which are characteristic for that particular molecule. The most primary vibrational states occur in the mid-infrared frequency region (i.e., 2.5-25 &mgr;m). However, non-invasive analyte determination in blood in this region is problematic, if not impossible, due to the absorption of the light by water. The problem is overcome through the use of shorter wavelengths of light which are not as attenuated by water. Overtones of the primary vibrational states exist at shorter wavelengths and enable quantitative determinations at these wavelengths.
It is known that glucose absorbs at multiple frequencies in both the mid- and near-infrared range. There are, however, other infrared active analytes in the blood which also absorb at similar frequencies. Due to the overlapping nature of these absorption bands, no single or specific frequency can be used for reliable non-invasive glucose measurement. Analysis of spectral data for glucose measurement thus requires evaluation of many spectral intensities over a wide spectral range to achieve the sensitivity, precision, accuracy, and reliability necessary for quantitative determination. In addition to overlapping absorption bands, measurement of glucose is further complicated by the fact that glucose is a minor component by weight in blood, and that the resulting spectral data may exhibit a non-linear response due to both the properties of the substance being examined and/or inherent non-linearities in optical instrumentation.
Another problem encountered in non-invasive skin based measurements of standard medical blood analytes in order to replace the need to draw blood from the patient has been the inherent differences between the concentration of a given analyte in the blood and the same analyte in the overall skin tissue water. Much of the work toward a replacement for blood drawing has been focused on the measurement of blood glucose in diabetic patients who must lance themselves four to five times per day in order to measure their capillary blood glucose concentration and adjust insulin therapy and meals. In the case of the infrared measurement, the beam “interrogates” a tissue volume that is largely water (70-80%).
However, blood, which is also approximately 80% water, makes up less than 10% of the tissue volume. Since glucose is not made, but only disposed of, in skin, all of the glucose in the water that bathes cells (interstitial fluid) and that is inside cells comes from the blood vessels. That is, blood glucose must move out of the blood vessels and into the surrounding interstitial water and then into cellular elements. This effect is, of course, time dependent as well as dependent upon the gradients, relative juxtaposition of the compartments, as well as the relative blood flow to the tissue. In short, the relationship between blood and tissue glucose concentration is very complex and variable even in a single subject. Thus, an integrated or summed measurement of total tissue water glucose concentration is often very different from the concentration of glucose in the small blood vessels that make up a fraction of the total tissue volume.
Glucose concentration measurement of interstitial fluid (the usually clear fluid that bathes all cells outside of blood vessels) as a surrogate for direct blood glucose concentration is problematic for some of the same reasons. Instead of measuring all compartments as with spectroscopic techniques, only one compartment is measured. Again, since glucose is only degraded in the skin (not manufactured), the interstitial space must be “filled” with glucose by the local blood vessels. This is analogous to a dye being slowly dripped into a glass of water, the faster the dye is dripped, the faster it reaches a high concentration or dark color throughout the total volume. As with any filling process, this is time dependent. Time lags between the concentration of glucose in interstitial fluid and blood have been documented ranging from zero to 60 minutes with an average lag of 20 minutes. Thus, the fact that the glucose must move between the tissue and blood causes errors in both interstitial space glucose and total tissue glucose concentration measurements.
When measurements of total tissue or interstitial glucose concentration and blood glucose concentration are made concurrently, the two are correlated, but the tissue glucose concentrations lag behind the blood levels. Blood or serum glucose concentrations must be delayed in order to overlay the interstitial or total glucose concentration. When blood glucose concentration is changing rapidly as might be expected in a diabetic after a meal high in simple carbohydrates (sugars) or after an insulin injection, the delay is more obvious and the difference between the blood and the other two measurements is most pronounced. The error between the blood measurement and the total or interstitial measurements is highest.
This presents obvious problems with respect to using the surrogate methods for monitoring and basing therapy in diabetic patients. Given the concentration difference, determining whether a given technique is working based on infrequent, discrete measurements is nearly impossible. Without continuous measurements, it is difficult to determine whether the patient's blood glucose is in a steady state condition or is in a flux; increasing or decreasing.
The worst case scenario in diabetic glucose management would be a quickly falling blood glucose concentration. Such a situation could result following a large insulin injection, unopposed by either glucose production in the liver or carbohydrate uptake from food in the gut. If a tissue measurement wer
Gardner Craig
Robinson Mark R.
Rohrscheib Mark
Crompton Seager & Tufte LLC
Rio Grande Medical Technologies, Inc.
Winakur Eric F.
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