# US 8,788,021 B1 · Live being optical analysis system and approach

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- Number: US 8,788,021 B1
- Document ID: US8788021B1
- Status: Granted
- Kind: B1
- Application number: 11/338,598
- Filed: 2006-01-24
- Granted: 2014-07-22
- Earliest claimed: 2005-01-24
- Assignees: The Board of Trustees of the Leland Stanford Junior Univerity
- Applicants: Benjamin A. Flusberg; Eric David Cocker; Juergen Claus Jung; Mark Jacob Schnitzer
- Inventors: Benjamin A. Flusberg; Eric David Cocker; Juergen Claus Jung; Mark Jacob Schnitzer
- Web page: https://patentgrep.com/patent/US8788021B1

## CPC

- A61B 5/0068: {Confocal scanning}
- A61B 5/0013: {Medical image data (A61B1/00011, A61B6/56, A61B8/56 take precedence)}
- A61B 5/0059: {using light, e.g. diagnosis by transillumination, diascopy, fluorescence (photoacoustic A61B5/0093; optical measurement of heart rate A61B5/02416; optical measurement of blood flow A61B5/0261; optical measurement of analytes A61B5/1455)}
- A61B 5/0062: {Arrangements for scanning}
- A61B 5/0064: {Body surface scanning}
- A61B 5/0071: {by measuring fluorescence emission}
- A61B 5/0079: {using mirrors, i.e. for self-examination}
- A61B 5/4064: {Evaluating the brain (for intracranial pressure A61B5/031; for cerebral blood gases A61B5/14553; using EEG A61B5/369)}
- A61B 5/6814: {Head}
- G01N 21/6408: {with measurement of decay time, time resolved fluorescence}
- G01N 21/6428: {Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" (in vivo A61B5/00; immunoassay G01N33/53)}
- G01N 21/6456: {Spatial resolved fluorescence measurements; Imaging}
- G01N 21/6486: {Measuring fluorescence of biological material, e.g. DNA, RNA, cells (G01N21/6428 takes precedence)}
- A61B 5/0075: {by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy (A61B5/0071 takes precedence)}
- A61B 2503/40: Animals
- A61B 2576/026: for the brain
- G01J 3/44: Raman spectrometry; Scattering spectrometry {; Fluorescence spectrometry}
- G01J 3/4406: {Fluorescence spectrometry}
- G01N 21/6458: {Fluorescence microscopy (fluorescence microscopes per se G02B21/0076 and G02B21/16)}
- 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)
- G01J: MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY (light sources F21, H01J, H01K, H05B; investigating properties of materials by optical means G01N)

## Abstract

Analysis of live beings is facilitated. According to an example embodiment of the present invention, a light-directing arrangement such as an endoscope is mounted to a live being. Optics in the light-directing arrangement are implemented to pass source light (e.g., laser excitation light) into the live being, and to pass light from the live being for detection thereof. The light from the live being may include, for example, photons emitted in response to the laser excitation light (i.e., fluoresced). The detected light is then used to detect a characteristic of the live being.

## Claims

### Claim 1

A method for in vivo analysis of a freely-moving live being, the method comprising;
a) fixing a housing to the live being, wherein the housing encloses therein a light-directing arrangement, wherein the light-directing arrangement comprises a light source to provide stimulation light, and wherein a combined weight of the housing and the light-directing arrangement comprising the light source is less than 4 grams;
b) passing stimulation light through the light-directing arrangement;
c) using the light-directing arrangement, providing the stimulation light to a target portion of the freely-moving live being while the freely-moving live being moves about, wherein said stimulation light induces response light from said target portion;
d) passing the response light from the target portion to a light detector;
e) at the light detector, receiving and detecting the response light, and generating a signal corresponding to the detected light; and
f) generating a cellular resolution image of said target portion using said signal.

### Claim 2 (depends on 1)

The method of claim 1, wherein providing the stimulation light to the target portion includes selectively scanning stimulation light across the target portion.

### Claim 3 (depends on 1)

The method of claim 1, wherein fixing the housing includes fixing the housing to the live being for a period of days, wherein providing stimulation light includes providing stimulation light at several instances over the period of days and wherein receiving and detecting the response light includes receiving and detecting the response of the live being to the stimulation light provided at the several instances.

### Claim 4 (depends on 3)

The method of claim 3, further comprising observing outward behavior of the live being over the period of days and comparing the detected response to the outward behavior.

### Claim 5 (depends on 3)

The method of claim 3, further comprising applying a treatment condition to the live being, wherein detecting the response of the live being includes detecting a response of the live being to the treatment condition.

### Claim 6 (depends on 1)

The method of claim 1, wherein the live being is one or more of the following: a genetically engineered animal, a transgenic animal, an animal having undergone delivery of viral vectors that encode proteins, or an animal having undergone delivery of RNAi.

### Claim 7 (depends on 1)

The method of claim 1, wherein the live being expresses a fluorescent protein and wherein providing the stimulation light to the target portion includes stimulating the fluorescent protein, and wherein receiving and detecting the response light includes detecting fluoresced photons from the fluorescent protein.

### Claim 8 (depends on 1)

The method of claim 1, further comprising injecting the live being with a molecule that facilitates a fluorescent response to the provided light, and detecting the fluorescent response.

### Claim 9 (depends on 1)

The method of claim 1, wherein providing the stimulation light includes providing pulsed laser light at a wavelength selected to facilitate nonlinear excitation of a fluorochrome in the live being.

### Claim 10 (depends on 9)

The method of claim 9, wherein receiving and detecting the response light includes detecting photons as a non-linear response of the target portion.

### Claim 11 (depends on 9)

The method of claim 9, wherein providing the pulsed laser light includes providing laser light having a wavelength that limits the fluorochrome excitation to a point of focus of the provided laser light.

### Claim 12 (depends on 1)

The method of claim 1, wherein said generating a cellular resolution image comprises fluorescence imaging.

### Claim 13 (depends on 12)

The method of claim 12, wherein said fluorescence imaging is selected from one or more of the following: confocal fluorescence imaging, multi-photon fluorescence imaging, fluorescence lifetime imaging, fluorescence resonance energy transfer, or fluorescence recovery after photobleaching.

### Claim 14 (depends on 12)

The method of claim 12, wherein said generating a cellular resolution image comprises types of polarization sensitive imaging.

### Claim 15 (depends on 1)

The method of claim 1, comprising generating a cellular resolution image while said live being is freely moving about as under regular living conditions.

### Claim 16 (depends on 1)

The method of claim 1, wherein the live being is a rat, bird, or mouse.

### Claim 17 (depends on 16)

The method of claim 16, wherein the live being is a mouse.

### Claim 18 (depends on 17)

The method of claim 17, wherein the housing is fixed onto a head of the mouse.

### Claim 19 (depends on 1)

The method of claim 1, wherein said target portion comprises brain tissue.

### Claim 20 (depends on 1)

The method of claim 1, wherein said response light is limited to a limited point of focus of said stimulation light to said target portion.

### Claim 21 (depends on 1)

The method of claim 1, comprising passing said stimulation light to said target portion while said freely moving live being is moving about said live being's home setting.

### Claim 22 (depends on 1)

The method of claim 1, wherein said light-directing arrangement is operably coupled via wireless links to an external device.

### Claim 23 (depends on 22)

The method of claim 22, wherein the external device is a computer which is configured to selectively control one or more components of the light directing arrangement.

### Claim 24 (depends on 1)

The method of claim 1, wherein said generating said image of said target portion occurs while said freely moving live being is generally free to move about as would under regular living conditions.

### Claim 25 (depends on 1)

The method of claim 1, further comprising holding the light-directing arrangement via a coupling in a position relative to the live being.

### Claim 26 (depends on 1)

The method of claim 1, wherein the light-directing arrangement comprising the light source and enclosed in the housing further comprises the light detector.

### Claim 27 (depends on 1)

The method of claim 1, wherein the light-directing arrangement comprising the light source and enclosed in the housing further comprises a GRIN lens.

### Claim 28 (depends on 27)

The method of claim 27, wherein the GRIN lens is about 30-1000 μM in diameter.

### Claim 29 (depends on 1)

The method of claim 1, wherein the light-directing arrangement comprising the light source and enclosed in the housing further comprises a MEMS mirror.

### Claim 30 (depends on 1)

The method of claim 1, wherein the light-directing arrangement comprising the light source and enclosed in the housing further comprises an objective lens.

### Claim 31 (depends on 1)

The method of claim 1, wherein the light-directing arrangement comprising the light source and enclosed in the housing further comprises a dichroic mirror.

### Claim 32 (depends on 1)

The method of claim 1, wherein the housing has a dimension of about 35 mm or less.

### Claim 33 (depends on 1)

The method of claim 1, wherein the housing comprises a base plate and a protective cover that is selectively removable from the base plate.