Non-invasive tissue glucose level monitoring

• US 20060195022A1
• Filed: 09/12/2005
• Published: 08/31/2006
• Est. Priority Date: 04/06/1998
• Status: Active Grant

• Current Assignee: Masimo Laboratories, Inc. (Masimo Corporation)
• Original Assignee: Masimo Laboratories, Inc. (Masimo Corporation)
• Inventors: Trepagnier, Pierre, Kollias, Nikiforos, Mansfield, James, Brand, Derek, Hopmeier, Michael J., Freeman, Jenny
• Granted Patent: US 7,899,518 B2
• Time in Patent Office: Days
• US Class Current: 600/316
• CPC Class Codes: A61B 5/0071 by measuring fluorescence emission
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/1455 using optical sensors, e.g. spectral photometrical oximeters

Abstract

Instruments and methods are described for performing non-invasive measurements of analyte levels and for monitoring, analyzing and regulating tissue status, such as tissue glucose levels.

Claims

1-90. -90. (canceled)

91. A non-invasive analyte monitoring instrument comprising:

a radiation source for directing excitation radiation to a portion of a surface of a tissue wherein said source emits radiation at a plurality of different wavelengths that excites a target in said tissue causing said target to emit radiation such that the radiation received at the surface provides an analyte level indication of the patient;

a radiation detector positioned to receive radiation emitted from the surface wherein said radiation detector is configured to synchronously scan radiation emitted by the target with the excitation radiation; and

a processing circuit operatively connected to the radiation detector that translates radiation received at the surface to a measurable signal to obtain said analyte level indication, wherein said radiation source comprises a visible light source or an ultraviolet light source,

wherein the target is selected from the group consisting of a structural matrix tissue component, a cellular tissue component, a mitochondrial tissue component, a collagen cross link, a pepsin-digestible collagen cross link, a collagenase-digestible collagen cross link, a non-pepsin digestible collagen cross link, an elastin cross link, a tryptophan-containing protein, NADH, FAD, a flavoprotein, and any combination thereof.

92. The instrument of claim 91 wherein the analyte is glucose.

93. The instrument of claim 91 wherein said portion of a tissue surface is at least about 0.5 square centimeters.

94. A non-invasive glucose monitoring instrument comprising:

a radiation source for directing excitation radiation to a portion of a tissue surface wherein said source emits excitation radiation at a plurality of different wavelengths comprising at least one wavelength of ultraviolet or visible light that excites a target to emit radiation, such that the radiation emitted from the excited target and received at the tissue surface correlates with a glucose level of the tissue;

a radiation detector positioned to receive the radiation emitted from the tissue surface wherein said radiation detector is configured to synchronously scan radiation emitted by the target with the excitation radiation; and

analyzing means operatively connected to the radiation detector for analyzing radiation detected by the radiation detector and translating said detected radiation to an indication of the tissue glucose level,

wherein the target is selected from the group consisting of a structural matrix tissue component, a cellular tissue component, a mitochondrial tissue component, a collagen cross link, a pepsin-digestible collagen cross link, a collagenase-digestible collagen cross link, a non-pepsin digestible collagen cross link, an elastin cross link, a tryptophan-containing protein, NADH, FAD, a flavoprotein, and any combination thereof.

95. The instrument of claim 94 wherein said analyzing means analyzes one or more parameters selected from the group consisting of wavelength of fluorescence, intensity, overall fluorescence, relative peak ratios, spectral shapes, peak shifts, band narrowing, band broadening and combinations thereof.

96. The instrument of claim 94 wherein said analyzing means comprises means for applying one or more multi variate analysis methodologies selected from the group consisting of PLS, PCR, LDA MLR, stepwise LR and combinations thereof.

97. The instrument of claim 94 further including a flexible-fiber optic arm that is configured to direct said excitation radiation to the target.

98. The instrument of claim 97 wherein the arm comprises a glass or a quartz fiber.

99. The instrument of claim 97 wherein the arm comprises lens apparatus.

100. The instrument of claim 94 wherein the portion of the tissue surface is a portion of the skin of a patient.

101. The instrument of claim 100 wherein the portion of skin irradiated is about 0.5 to 4 square centimeters.

102. The instrument of claim 94 wherein said radiation source comprises means for applying said radiation source to the tissue surface at a constant pressure.

103. The instrument of claim 94 wherein the plurality of different wavelengths comprises an excitation wavelength of about 295 nm.

104. The instrument of claim 94 wherein the plurality of different wavelengths comprises an excitation wavelength of between about 330-370 nm.

105. The instrument of claim 94 wherein the target is a structural matrix component.

106. The instrument of claim 94 wherein the target is a cellular component.

107. The instrument of claim 94 wherein the target is a mitochondrial component.

108. The instrument of claim 94 wherein the target is a collagen cross link.

109. The instrument of claim 108 wherein the target is a pepsin-digestible or a collagenase-digestible collagen cross link.

110. The instrument of claim 94 wherein the target is tryptophan-containing proteins.

111. The instrument of claim 94 wherein the target is NADH.

112. The instrument of claim 94 wherein the target is FAD or another flavoprotein.

113. The instrument of claim 94 wherein the target is a combination of fluorophores selected from the group consisting of a pepsin-digestible collagen cross link, a collagenase-digestible collagen cross link, a non-pepsin digestible collagen cross link, tryptophan-containing proteins, elastin cross links, FAD and NADH.

114. The instrument of claim 94 wherein the radiation received at the surface has been quenched or amplified by one or more matrix, cellular, or mitochondrial components, or any other cellular component reflective of metabolic activity, in the tissue.

115. The instrument of claim 94 wherein the radiation received at the surface has been quenched or amplified by a fluorescent cellular energy component or a shift in equilibrium of said cellular energy component.

116. The instrument of claim 94 further comprising a display operatively connected to the analyzing means that is operative to display said glucose level indication.

117. The instrument of claim 94 wherein said analyzing means further comprises means for monitoring a trend in glucose levels and said instrument further comprises a device responsive to the analyzing means that is operative to administer a medication to a patient at a rate that corresponds to the indicated glucose level.

118. The instrument of claim 117 wherein the medication is glucose or insulin and the device is a pump.

119. The instrument of claim 94 further comprising an alarm means operationally coupled to the analyzing means wherein the alarm means is activated when the indicated glucose concentration exceeds a first predetermined value, falls below a second predetermined value or varies more than a predetermined amount from a third predetermined value.

120. The instrument of claim 119 wherein the first, second or third predetermined value is 20%.

121. The instrument of claim 94 further comprising means for measuring scattering.

122. The instrument of claim 121 wherein the means for measuring scattering comprises an illuminating means that emits radiation at an angle greater than 60 degrees to said target.

123. The instrument of claim 121 wherein the means for measuring scattering comprises an illuminating means which emits radiation at between about 330 to 420 nm.

124. The instrument of claim 121 wherein the means for measuring scattering comprises an illuminating means which emits radiation at between about 320 to 800 nm.

125. The instrument of claim 121 further comprising means for measuring absorbance and wherein said analyzing means comprises means for adjusting the indicated glucose concentration based on the scattering and absorbance measured.

126. A non-invasive method of detecting a glucose level of a tissue comprising:

exciting a non-glucose target in the tissue with ultraviolet radiation or visible light at a plurality of different wavelengths, wherein the excited target emits radiation such that the radiation received at a tissue surface is indicative of a glucose level of a patient;

detecting radiation by synchronously scanning radiation emitted by the target and transmitted through the intervening tissue to the surface; and

determining said glucose level from the radiation detected;

wherein the target is selected from the group consisting of pepsin-digestible collagen cross link, a collagenase-digestible collagen cross link, a non-pepsin digestible collagen cross link, tryptophan-containing proteins, elastin cross links, FAD, flavoproteins, NADH and combinations thereof.

127. The method of claim 126 wherein the target is excited with electromagnetic radiation.

128. The method of claim 126 wherein the plurality of different wavelengths comprises an excitation wavelength of about 295 nm.

129. The method of claim 126 wherein the plurality of different wavelengths comprises an excitation wavelength of between about 335-340 nm.

130. The method of claim 126 wherein the radiation emitted by the target is fluorescent radiation.

131. The method of claim 126 further comprising adjusting the glucose level of the patient in response to the glucose level or trend determined.

132. The method of claim 126 further comprising administering insulin to the patient.

133. The method of claim 132 wherein insulin is administered with a biodelivery system.

134. The method of claim 126 further comprising actuating an alarm in response to the glucose level when said glucose level exceeds a predetermined first level, falls below a predetermined second level or varies more than a predetermined amount from a predetermined third level.

135. The instrument of claim 134 wherein the first, second or third predetermined value is 20%.

136. The method of claim 126 wherein the step of exciting comprises application of a probe to the skin, said probe comprising a radiation source.

137. A method for detecting diabetes in a patient comprising;

exciting a non-glucose target using ultraviolet and visible radiation at a plurality of different wavelenghts;

detecting radiation by synchronously scanning radiation emitted by the target;

determining said glucose level from the radiation detected; and

detecting diabetes based on said determined glucose level.

138. An instrument for assessing changes in a structural matrix, cellular, or mitochondrial of the skin of a patient comprising:

means for irradiating a tissue with a plurality of wavelengths of excitation light;

means for synchronously scanning the fluorescence emitted from the skin with the excitation light;

means for measuring said fluorescence emitted from the skin;

means for measuring scattering; and

means for measuring absorbance.

139. The instrument of claim 138 wherein said means for measuring fluorescence comprises measuring one or more parameters selected from the group consisting of wavelength of fluorescence, intensity, overall fluorescence, relative peak ratios, spectral shapes, peak shifts, band narrowing, band broadening and combinations thereof.

140. A non-invasive method of assessing a change in the structural matrix, cellular, or mitochondrial of a tissue comprising:

exposing the tissue to radiation at a first wavelength;

detecting fluorescence emitted by exposed tissue;

exposing the tissue to radiation of a second wavelength;

detecting a scattering re-emitted from the exposed tissue; and

deriving an indication representative of the change in the structural matrix of the tissue based on the fluorescence detected and the scattering detected.

141. The method of claim 140 wherein the step of detecting fluorescence comprises detecting one or more parameters selected from the group consisting of wavelength of fluorescence, intensity, overall fluorescence, relative peak ratios, spectral shapes, peak shifts, band narrowing, band broadening and combinations thereof.

142. The method of claim 141 wherein said change correlates with a condition.

143. The method of claim 142 wherein the condition is selected from the group consisting of cancer, age, diabetes, photodamage, presence of topical steroids and infections.

144. The method of claim 140 further comprising detecting absorbance.

145. The method of claim 140 wherein the first wavelength is between about 320 and 420 nm.

146. The method of claim 140 wherein the second wavelength is between about 330 and 420 nm.

147. The method of claim 140 wherein the first wavelength and the second wavelength are the same.

148. The method of claim 140 wherein the wavelength region is a subset of the region of 280-800 nm.

149. The method of claim 140 wherein the tissue is skin or mucosa.

150. An instrument for assessing changes in the environment of the matrix, cellular, or mitochondrial components, or other cellular components reflective of metabolic activity, of a tissue comprising:

means for irradiating a tissue with a plurality of wavelengths of excitation light;

means for synchronously scanning the fluorescence emitted from the skin with the excitation light;

means for measuring said fluorescence emitted from the skin;

means for measuring scattering; and

means for measuring absorbance.

151. A non-invasive method of assessing a change in the environment of the matrix, cellular, or mitochondrial components, or other cellular components reflective of metabolic activity, of a tissue comprising:

exposing the tissue to radiation at a first wavelength;

detecting fluorescence emitted by exposed tissue;

exposing the tissue to radiation of a second wavelength;

detecting scattering re-emitted from the exposed tissue;

detecting absorbance; and

deriving an indication representative of the change in the environment of the matrix, cellular, or mitochondrial components, or other cellular components reflective of metabolic activity, of the tissue based on the fluorescence detected, the scattering detected and the absorbance detected.

152. A non-invasive method for monitoring skin or tissue constituents in which information about or signature of a specific blood analyte level or disease process is provided comprising the steps of:

exciting a target fluorophore;

detecting radiation emitted by the fluorophore and transmitted through intervening tissue to the surface; and

determining said information or signature from the radiation detected.