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(12) United States Patent (10) Patent No.: US 6,319,682 B1 Hochman (45) Date of Patent: *Nov

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(12) United States Patent (10) Patent No.: US 6,319,682 B1 Hochman (45) Date of Patent: *Nov USOO6319682B1 (12) United States Patent (10) Patent No.: US 6,319,682 B1 Hochman (45) Date of Patent: *Nov. 20, 2001 (54) METHODS AND SYSTEMS FOR ASSESSING (51) Int. Cl." ............................... C12O 1/02; C12O 1/00; BIOLOGICAL MATERIALS USING OPTICAL C12O 1/24; C12O 1/18 AND SPECTROSCOPIC DETECTION (52) U.S. Cl. ................................... 435/29; 435/4; 435/30; TECHNIQUES 435/288.7; 435/32 (58) Field of Search .................................... 435/29, 4, 30, (75) Inventor: Daryl W. Hochman, Seattle, WA (US) 435/288.7, 32 (73) Assignee: Cytoscan Sciences, L.L.C., Seattle, WA (56) References Cited US (US) U.S. PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this 5,585,401 12/1996 Bandt et al. ......................... 514/562 patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. FOREIGN PATENT DOCUMENTS 2000037616 12/1999 (WO) ..................................... 435/29 This patent is Subject to a terminal dis claimer. * cited by examiner Primary Examiner Louise N. Leary (21) Appl. No.: 09/629,046 (74) Attorney, Agent, or Firm-Ann W. Speckman (22) Filed: Jul. 31, 2000 (57) ABSTRACT Related U.S. Application Data Optical detection techniques for the assessment of the physi ological State, health and/or viability of biological materials (63) Continuation-in-part of application No. 09/326,008, filed on are provided. Biological materials which may be examined Jun. 4, 1999, now Pat. No. 6,096.510, which is a continu- using Such techniques include cells, tissues, organs and ation-in-part of application No. 08/949,416, filed on Oct. 14, Subcellular components. The inventive techniques may be 1997, now Pat. No. 5,976,825, which is a continuation of emploved in high throughput Screening of potential diag application No. 08/539,296, filed on Oct. 4, 1995, now Pat. ploy 9. gnp 9. p 9. No. 5,902,732. nostic and/or therapeutic agents. (60) Provisional application No. 60/088,494, filed on Jun. 8, 1998. 53 Claims, 11 Drawing Sheets U.S. Patent Nov. 20, 2001 Sheet 1 of 11 US 6,319,682 B1 ::::::::::::::::: U.S. Patent Nov. 20, 2001 Sheet 2 of 11 US 6,319,682 B1 3.88. U.S. Patent Nov. 20, 2001 Sheet 3 of 11 US 6,319,682 B1 FSR U.S. Patent Nov. 20, 2001 Sheet 4 of 11 US 6,319,682 B1 *:::::::: :::::::::: : 88. ----------------...-3- 3. X 3 S. U.S. Patent Nov. 20, 2001 Sheet 5 of 11 US 6,319,682 B1 FIGURE 4C -ee-ee-e BOX 1 A-A-A-AA-A BOX 4 r s O N s S. es 38. 32 s. R l () Z 1. O (/) CC Z Lll (D 2. T O ---T-t-t- -- - - - - T ------- OOO 2OOO 4OOO 6OOO 8OOO SECONDS FIGURE 4D o-o-o-o-aBOX 1 9-o-o-o-do BOX 2 0.04 l O 2 O O) Z OOO (D 2. is -0.02 O 000 20. 40.OO 60.00 SECONDS U.S. Patent Nov. 20, 2001 Sheet 6 of 11 US 6,319,682 B1 3883 & U.S. Patent Nov. 20, 2001 Sheet 7 of 11 US 6,319,682 B1 :*:3:3: S3 :::::: 83. :3:33:8; 8. :::38: 83 3.33:8: 8: ; ::: 38. 3.33E 88. *:::::: S-8 U.S. Patent Nov. 20, 2001 Sheet 8 of 11 US 6,319,682 B1 :::::::::: -; U.S. Patent Nov. 20, 2001 Sheet 9 of 11 US 6,319,682 B1 U.S. Patent Nov. 20, 2001 Sheet 10 of 11 US 6,319,682 B1 TIME (EACH DIV = 2 SEC) FIGURE 9A i TIME (EACH DiV = 2 SEC) FIGURE 9B U.S. Patent Nov. 20, 2001 Sheet 11 of 11 US 6,319,682 B1 US 6,319,682 B1 1 2 METHODS AND SYSTEMS FOR ASSESSING functions, the time course of the physiological effect, gen BIOLOGICAL MATERIALS USING OPTICAL eral cell or tissue health, or the like. AND SPECTROSCOPIC DETECTION Optical techniques have been developed and used for TECHNIQUES Several applications. Light Scattering has been used in the past to provide measurements of OSmotic water permeability REFERENCE TO RELATED APPLICATIONS in Suspensions of osmotically responsive vesicles and Small This application is a continuation-in-part application of cells. A. S. Verkman, “Optical Methods to Measure Mem U.S. patent application Ser. No. 09/326,008, filed Jun. 4, brane Transport Processes,” J. Membrane Biol. 148:99-110, 1999, now U.S. Pat. No. 6,096,510, issued Aug. 1, 2000, 1995. Another study reported a method for the optical which is a continuation-in-part of U.S. patent application measurement of OSmotic water transport in cultured cells. M. Ser. No. 08/949,416, filed Oct. 14, 1997, now U.S. Pat. No. Echevairia, A. S. Verkman, “Optical Measurement of 5,976,825, issued Nov. 2, 1999, which is a continuation of Osmotic Water Transport in Cultured Cells: Role of Glucose U.S. patent application Ser. No. 08/539,296, filed Oct. 4, Transporters,” J. Gen. Physiol. 99:573–589, 1992. 1995, now U.S. Pat. No. 5,902,732, issued May 11, 1999. Optical techniques for observing nerve activity and neu This application claims benefit of Ser. No. 60/088,494, filed 15 ronal tissue are well-established. Hill and Keynes observed Jun. 8, 1998. that the nerve from the waking leg of the Shore crab normally has a whitish opacity caused by light Scattering, FIELD OF THE INVENTION and that opacity changes evoked by electrical Stimulation of that nerve were measurable. Hill, D. K. and Keynes, R. D., The methods and Systems of the present invention employ “Opacity Changes in Stimulated Nerve,” J. Physiol. optical, or spectroscopic, detection techniques for assessing 108:278-281, 1949. Since the publication of those results, the health, physiological condition, and viability of biologi experiments designed to learn more about the physiological cal materials. Such as tissues, cells, and Subcellular mechanisms underlying the correlation between optical and components, and may be used in both in vitro and in vivo electrical properties of neuronal tissue and to develop Systems. One important application of the methods and 25 improved techniques for detecting and recording activity apparatus of the present invention is high throughput Screen evoked optical changes have been ongoing. ing of candidate agents and conditions to evaluate their Suitability as diagnostic or therapeutic agents. Intrinsic changes in optical properties of cortical tissue have been assessed by reflection measurements of tissue in response to electrical or metabolic activity. Grinvald, A., et BACKGROUND OF THE INVENTION al., “Functional Architecture of Cortex Revealed by Optical Drug development programs rely on in vitro Screening Imaging of Intrinsic Signals,” Nature 324:361-364, 1986; assays and Subsequent testing in appropriate animal models Grinvald, et al., “Optical Imaging of Neuronal Activity, to evaluate drug candidates prior to conducting clinical trials Physiological Reviews, Vol. 68, No. 4, October 1988. Grin using human Subjects. Screening methods currently used are Vald and his colleagues reported that Some slow Signals from generally difficult to Scale up to provide the high throughput 35 hippocampal Slices could be imaged using a CCD camera Screening necessary to test the numerous candidate com without Signal averaging. pounds generated by traditional and computational means. A CCD camera was used to detect intrinsic Signals in a Moreover, Studies involving cell culture Systems and animal monkey model. Ts'o, D. Y., et al., “Functional Organization model responses frequently don’t accurately predict the 40 of Primate Visual Cortex Revealed by High Resolution responses and Side effects observed during human clinical Optical Imaging,” Science 249:417-420, 1990. The tech trials. nique employed by Ts'o et al. Would not be practical for Conventional methods for assessing the effects of various human clinical use, Since imaging of intrinsic Signals was agents or physiological activities on biological materials, in achieved by implanting a stainleSS Steel optical chamber in both in vitro and in Vivo Systems, generally are not highly 45 the skull of a monkey and contacting the cortical tissue with Sensitive or informative. For example, assessment of the an optical oil. Furthermore, in order to achieve Sufficient effect of a physiological agent, Such as a drug, on a popu Signal to noise ratios, Ts'o, et al., had to average images over lation of cells or tissue grown in culture, conventionally periods of time greater than 30 minutes per image. provides information relating to the effect of the agent on the The mechanisms responsible for intrinsic Signals are not cell or tissue population only at Specified points in time. 50 well understood. Possible Sources of intrinsic Signals include Additionally, current assessment techniques generally pro dilation of small blood vessels, changes in blood flow, vide information relating to a single or a Small number of Volume and oxygenation, neuronal activity-dependent parameters. Candidate agents are Systematically tested for release of potassium, and Swelling of neurons and/or glial cytotoxicity, which may be determined as a function of cells caused, for example, by ion fluxes or osmotic activity. concentration. A population of cells is treated and, at one or 55 Light having a wavelength in the range of 300 to 3000 nm Several time points following treatment, cell Survival is may also be reflected differently between active and quies measured. Cytotoxicity assays generally do not provide any cent tissue due to increased blood flow into regions of higher information relating to the cause(s) or time course of cell neuronal activity. Yet another factor which may contribute to death. intrinsic signals is a change in the ratio of oxyhemoglobin Similarly, agents are frequently evaluated based on their 60 and deoxyhemoglobin in blood.
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