# US 10,478,106 B2 · Probe, system, and method for non-invasive measurement of blood analytes

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- Number: US 10,478,106 B2
- Document ID: US10478106B2
- Status: Granted
- Kind: B2
- Application number: 15/026,312
- Filed: 2014-10-01
- Published: 2016-08-18
- Granted: 2019-11-19
- Earliest claimed: 2013-10-02
- Assignees: Nederlandse Organisatie voor toegepast-natuurwetenschappelijk onderzoek TNO
- Applicants: Nederlandse Organisatie voor toegepast-natuurwetenschappelijk onderzoek TNO
- Inventors: Daniel Perez Calero; James Peter Robert Day; Jacobus Thomas Wilhelmus Elisabeth Vogels; Maarten J. Scholtes-Timmerman; Jacobus Johannes Frederik van Veen
- Web page: https://patentgrep.com/patent/US10478106B2

## CPC

- A61B 5/1455: using optical sensors, e.g. spectral photometrical oximeters
- A61B 5/0075: {by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy (A61B5/0071 takes precedence)}
- A61B 5/1451: {for interstitial fluid}
- A61B 5/14532: {for measuring glucose, e.g. by tissue impedance measurement}
- A61B 5/14546: {for measuring analytes not otherwise provided for, e.g. ions, cytochromes}
- A61B 5/14551: {for measuring blood gases}
- A61B 5/6847: {mounted on an invasive device}
- A61B 2090/306: {using optical fibres}
- A61B 2503/40: Animals
- A61B 2562/0238: Optical sensor arrangements for performing transmission measurements on body tissue
- A61B 2562/185: Optical shielding, e.g. baffles
- A61B 2576/00: Medical imaging apparatus involving image processing or analysis (A61B1/00009, A61B6/52 and A61B8/52 take precedence)
- G01N 21/65: Raman scattering
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present disclosure concerns a measuring probe (10) for non-invasive in vivo measurement of blood analytes (33) by Raman spectroscopy. The measuring probe (10) comprises a housing (20) having a skin engaging surface (21). The housing (20) comprises a first optical system (1, 3, 4) arranged for providing source light (11) to the skin engaging surface (21) for penetrating a subject's skin (31) by said source light (11) for interacting with the blood analytes (33). The housing (20) further comprises a second optical system (5, 6, 2) arranged for capturing scattered Raman light (12) from the blood analytes (33) for measurement of the blood analytes (33). The first optical system (1, 3, 4) is arranged for providing the source light (11) as a collimated beam (1c) onto the skin (31).

## Claims

### Claim 1

A measuring probe for non-invasive in vivo measurement of blood analytes by Raman spectroscopy, the measuring probe comprising a housing having a skin engaging surface for engaging a subject's skin, the housing comprising:
a first optical system comprising light guiding optics configured to direct source light, as a collimated beam, to the skin engaging surface and further configured to cause penetration of the subject 'skin with said collimated beam, for interacting of the collimated beam with the blood analytes, wherein angles between rays of light in the collimated beam are within a threshold value of 10 degrees; and
a second optical system configured to collect scattered Raman light, obtained from scattering of the collimated beam by the blood analytes, for use in measurement of the blood analytes;
wherein the first optical system is configured to direct the collimated beam at an oblique incidence angle with respect to a normal incidence angle of the skin engaging surface; and
wherein the second optical system is configured to spatially separate the scattered Raman light from a specular reflection of the collimated beam from the subject's skin.

### Claim 2 (depends on 1)

The measuring probe according to claim 1, wherein an entrance of the second optical system is arranged outside a path of the specular reflection for preventing said specular reflection from entering the second optical system.

### Claim 3 (depends on 2)

The measuring probe according to claim 2, wherein the entrance of the second optical system is arranged at a distance from the skin engaging surface, wherein the collimated beam of source light is passed by a first mirror underneath collection optics of the second optical system, between the entrance and the skin engaging surface, and reflected by a second mirror adjacent the collection optics at the skin engaging surface as the collimated beam to illuminate a surface of the subject's skin.

### Claim 4 (depends on 2)

The measuring probe according to claim 2, wherein the entrance of the second optical system is configured to face towards a surface of the subject's skin that illuminated by said collimated beam, such that at least a majority of the scattered Raman light collected by the second optical system is light that emanates from said surface of the subject's skin, wherein said surface of the subject's skin that is illuminated by side collimated beam has an area of more than 5 mm2.

### Claim 5 (depends on 1)

The measuring probe according to claim 1, wherein the first optical system comprises a first optical fibre bundle and said light guiding optics, wherein the first optical fibre bundle is configured to project said collimated beam onto the light guiding optics, and the light guiding optics are configured to direct the collimated beam onto the subect's skin.

### Claim 6 (depends on 1)

The measuring probe according to claim 1, wherein the second optical system comprises imaging optics and a second optical fibre bundle, wherein the second optical system is configured to project an image of an illuminated pattern on the subject's skin, which is illuminated by the collimated beam, onto an entrance of the second optical fibre bundle.

### Claim 7 (depends on 1)

A measuring system for non-invasive in vivo measurement of blood analytes by Raman spectroscopy, the measuring system comprising:
the measuring probe according to claim 1;
a light source configured to provide the source light to the measuring probe;
a spectrometer configured to receive the scattered Raman light from the measuring probe and projecting a Raman spectrum of the scattered Raman light;
a photodetector configured to measure the Raman spectrum;
a processor configured to read out measurement data from the photodetector and calculating a presence and/or concentration of the blood analytes based on the Raman spectrum.

### Claim 8 (depends on 7)

The measuring system according to claim 7, wherein the measuring probe is connected to the light source and/or spectrometer by flexibly moveable optical fibres wherein the measuring probe is substantially free to move and/or rotate with respect to the light source and/or spectrometer within a range of the optical fibres therein between.

### Claim 9 (depends on 7)

The measuring system according to claim 7, wherein an optical path between a measuring spot on the skin and the spectrometer is connected by an optical fibre bundle, wherein an input end of the fibre bundle is shaped in a circular pattern to receive a projection of the measuring spot and an output end of the fibre bundle is shaped as an elongate line pattern to provide input to the spectrometer.

### Claim 10 (depends on 7)

The measuring system according to claim 7, wherein the processor is configured to pre-process the measurement data for subtracting a background, wherein the pre-processing comprises a combination of time-dependent noise suppression and subtraction of a modelled constant background.

### Claim 11 (depends on 10)

The measuring system according to claim 10, wherein the modelled constant background is modelled by polynomial fitting.

### Claim 12 (depends on 7)

The measuring system according to claim 7, wherein a Raman signal is extracted from the measurement data by multi-variate regression.

### Claim 13 (depends on 7)

The measuring system according to claim 7, wherein the spectrometer is a monolithic spectrometer comprising a body of solid material having optical surfaces configured to guide the scattered Raman light along an optical path inside the body.

### Claim 14 (depends on 7)

The measuring system according to claim 7, wherein the system is arranged for detecting glucose as blood analytes.

### Claim 15

A method for non-invasive in vivo measurement of blood analytes by Raman spectroscopy, the method comprising:
directing source light as a collimated beam, using light guiding optics, to penetrate a subject's skin with said collimated beam for interacting of the collimated beam with the blood analytes, wherein angles between rays of light in the collimated beam are within a threshold value of 10 degrees; and
collecting scattered Raman light, obtained from scattering of the collimated beam by the blood analytes, for use in measurement of the blood analytes;
wherein the collimated beam is directed at an oblique incidence angle with respect to a normal incidence angle of the subject's skin; and
wherein the scattered Raman light is spatially separated from a specular reflection of the collimated beam from the subject's skin.