CA2331986A1

CA2331986A1 - In-vivo determining the effects of a pharmaceutical on blood parameters

Info

Publication number: CA2331986A1
Application number: CA002331986A
Authority: CA
Inventors: Kenneth Kensey
Original assignee: Individual
Current assignee: Rheologics Inc
Priority date: 1997-08-28
Filing date: 1999-06-22
Publication date: 1999-12-29
Also published as: CA2301161A1; CN1273634A; US6659965B1; CN1305355A; US6077234A; IL140106A0; WO1999066839A1; US6443911B1; NO20000944L; US6152888A; AU737207B2; HUP0100201A3; US6261244B1; US20020169370A1; NO20006467D0; NO20006467L; AU4579799A; NZ502905A; US6805674B2; NO20000944D0

Abstract

A blood viscosity measuring system and method that monitors the rising head of a column of fluid (42) representing a living being's blood in-vivo to determine the blood viscosity over a range of shears. The system includes a capillary tube (26), at least a portion of which is located within the vascular system (30) of the being, and a riser tube (44), having a liquid therein coupled to the capillary tube. A sensor (48, 50) and associated microprocessor (52) are provided to determine the change in the height of the liquid in the riser tube (44) at plural points along the length of the tube from which the viscosity is calculated. The system can be utilized to determine the deformability of the red blood cells of a living being's blood and/or the thixotropic properties of a living being's blood. Use of the system enables one to screen a pharmaceutical or other compound on a test subject, such as a living human being or laboratory animal, to determine the likely effect of the pharmaceutical in altering a parameter of the blood, e.g., viscosity, red blood cell deformability, or thixotropic nature, of a living, e.g., human, being to which the pharmaceutical will ultimately be administered.

Description

I
IN-VIVO DETERMINING THE EFFECTS OF A PHARMACEUTICAL ON BLOOD PARAMETERS
SPECIFICATION
BACKGROUND OF THE INVENTION
This invention relates generally to an apparatus and methods for measuring the viscosity of liquids, and more particularly, an apparatus and methods for measuring the viscosity of the blood of a living being in-vivo and over a wide range of shears.
The importance of determining the viscosity of blood is well-known. Fibro~en.
Viscosity and White Blood Cell Count Are Major Risk Factors for Ischemic Heart Disease, by Yarnell et al., Circulation, Vol. 83, No. 3, March 1991; Post~randial Changes in Plasma and Serum Viscosity and Plasma Lipids and Lipoproteins Af3er an Acute Test Meal,by Tangney, et al., American Journal for Clinical Nutrition, 65:36-40, 1997; Studies of Plasma Viscosity in Primary Hvnerlipoproteinaemia, by Leonhardt et al., Atherosclerosis 28, 29-40, 1977;
Effects of Lipoproteins on Plasma Viscosity, by Seplowitz, et al., Atherosclerosis 38, 89-95, 1981;
HvDerviscosity Syndrome in a Hypercholesterolemic Patient with Primary Biliarv Cirrhosis, Rosenson, et al., Gastroenterology, Vol. 98, No. 5, 1990; Blood Viscosity and Risk of Cardiovascular Eventsahe Edinburgh Artery Study, by Lowe et al., British Journal of Hematology, 96, 168-171, 1997; Blood Rheol~gy Associated with Cardiovascular Risk Factors and Chronic Cardiovascular Diseases: Results of an Epidemiolo~ic Cross-Sectional Study, by Koenig, et al., Angiology, The Journal of Vascular Diseases, November 1988;
Importance of Blood Viscoelasticity in Arteriosclerosis, by Hell, et al., Angiology, The Journal of Vascular Diseases, June, 1989; Thermal Method for Continuous Blood-Velocity Measurements in Large Blood Vessels, and Cardiac-Output Determination, by Delanois, Medical and Biological Engineering, Vol. 1 l, No. 2, March 1973; Fluid Mechanics in Atherosclerosis, by Nerem, et al., Handbook of Bioengineering, Chapter 21, 1985.
Much effort has been made to develop apparatus and methods for determining the viscosity of blood. Theor~and Desi n~ of Disposable Clinical Blood Viscometer, by Litt et al., Biorheology, 25, 697-712, 1988; Automated Measurement of Plasma Viscosit~~pillarv Viscometer, by Cooke, et al., Journal of Clinical Pathology 41, 1213-1216, 1988; A Novel Computerized Viscometer/Rheometer by Jimenez and Kostic, Rev. Scientific Instruments 65,

2 Vol 1, January 1994; A New Instrument for the Measurement of Plasma-Viscosity, by John Harkness, The Lancet, pp. 280-281, August 10, 1963; Blood Viscosity and Ravnaud's Disease.
by Pringle, et al., The Lancet, pp. 1086-1089, May 22, 1965; Measurement of Blood Viscosity Usins a Conicylindrical Viscometer, by Walker et al., Medical and Biological Engineering, pp.
551-557, September 1976.
In addition, there are a number of patents relating to blood viscosity measuring apparatus and methods. See for example, U.S. Patent Nos.: 3,342,063 (Smythe et al.);

3,720,097 (Kron);
3,999,538 (Philpot, Jr.); 4,083,363 (Philpot); 4,149,405 (Ringrose); 4,165,632 (Weber, et. al.);

4,517,830 (Gunn, deceased, et. al.); 4,519,239 (Kiesewetter, et. al.);
4,554,821 (Kiesewetter, et. al.); 4,858,127 (Kron, et. al.); 4,884,577 (Merrill); 4,947,678 (Hori et al.); 5,181,415 (Esvan et al.); 5,257,529 (Taniguchi et al.); 5,271,398 (Schlain et al.); and

5,447,440 (Davis, et. al.).
The Smythe '063 patent discloses an apparatus for measuring the viscosity of a blood sample based on the pressure detected in a conduit containing the blood sample. The Kron'097 patent discloses a method and apparatus for determining the blood viscosity using a flowmeter, a pressure source and a pressure transducer. The Philpot '538 patent discloses a method of determining blood viscosity by withdrawing blood from the vein at a constant pressure for a predetermined time period and from the volume of blood withdrawn. The Philpot'363 patent discloses an apparatus for determining blood viscosity using a hollow needle, a means for withdrawing and collecting blood from the vein via the hollow needle, a negative pressure measuring device and a timing device. The Ringrose '405 patent discloses a method for measuring the viscosity of blood by placing a sample of it on a support and directing a beam of light through the sample and then detecting the reflected light while vibrating the support at a given frequency and amplitude. The Weber'632 patent discloses a method and apparatus for determining the fluidity of blood by drawing the blood through a capillary tube measuring cell into a reservoir and then returning the blood back through the tube at a constant flow velocity and with the pressure difference between the ends of the capillary tube being directly related to the blood viscosity. The Gunn'830 patent discloses an apparatus for determining blood viscosity that utilizes a transparent hollow tube, a needle at one end, a plunger at the other end for creating a vacuum to extract a predetermined amount and an apertured weight member that is movable within the tube and is movable by gravity at a rate that is a function of the viscosity of the blood.
The Kiesewetter '239 patent discloses an apparatus for determining the flow shear stress of suspensions, principally blood, using a measuring chamber comprised of a passage configuration that simulates the natural microcirculation of capillary passages in a being.
The Kiesewetter'821 patent discloses another apparatus for determining the viscosity of fluids, particularly blood, that includes the use of two parallel branches of a flow loop in combination with a flow rate measuring device for measuring the flow in one of the branches for determining the blood viscosity. The Kron '127 patent discloses an apparatus and method for determining blood viscosity of a blood sample over a wide range of shear rates. The Mernll'S77 patent discloses an apparatus and method for determining the blood viscosity of a blood sample using a hollow column in fluid communication with a chamber containing a porous bed and means for measuring the blood flow rate within the column. The Hori'678 patent discloses a method for measurement of the viscosity change in blood by disposing a temperature sensor in the blood flow and stimulating the blood so as to cause a viscosity change. The Esvan '415 patent discloses an apparatus that detects the change in viscosity of a blood sample based on the relative slip of a drive element and a driven element, which holds the blood sample, that are rotated. The Taniguchi'S29 patent discloses a method and apparatus for determining the viscosity ofliquids, e.g., a blood sample, utilizing a pair of vertically-aligned tubes coupled together via fine tubes while using a pressure sensor to measure the change of an internal tube pressure with the passage of time and the change of flow rate of the blood. The Bedingham '328 patent discloses an intravascular blood parameter sensing system that uses a catheter and probe having a plurality of sensors (e.g., an OZ sensor, CO~ sensor, etc.) for measuring particular blood parameters in vivo. The Schlain '398 patent discloses a intra-vessel method and apparatus for detecting undesirable wall effect on blood parameter sensors and for moving such sensors to reduce or eliminate the wall effect. The Davis'440 patent discloses an apparatus for conducting a variety of assays that are responsive to a change in the viscosity of a sample fluid, e.g., blood.
Viscosity measuring devices and methods for fluids in general are well-known.
See for example, U.S. Patent Nos.: 1,810,992 (Dallwitz-Wegner); 2,343,061 (Irany);
2,696,734 (Brunstrum et al.); 2,700,891 (Shafer); 2,934,944 (Eolkin); 3,071,961 (Heigl et al.}; 3,116,630 (Piros); 3,137,161 (Lewis et al.); 3,138,950 (Welty et al.); 3,277,694 (Cannon et al.); 3,286,511 (Harkness); 3,435,665 (Tzentis); 3,520,179 (Reed); 3,604,247 (Gramain et al.);
3,666,999 (Moreland, Jr. et al.); 3,680,362 (Geerdes et al.); 3,699,804 (Gassmann et al.); 3,713,328 (Aritomi); 3,782,173 (Van Vessem et al.); 3,864,962 (Stark et al.); 3,908,441 (Virloget);

3,952,577 (Hayes et aL); 3,990,295 (Renovanz et al.); 4,149,405 (Ringrose);
4,302,965 (Johnson et al.); 4,426,878 (Price et al.); 4,432,761 (Dawe); 4,616,503 {Plungis et al.); 4,637,250 (Irvine, Jr. et al.); 4,680,957 (Dodd); 4,680,958 (Ruelle et al.); 4,750,351 (Ball);
4,856,322 (Langrick et al.); 4,899,575 (Chu et al.); 5,142,899 (Park et al.); 5,222,497 (Ono);
5,224,375 (You et aL);
5,257,529 (Taniguchi et al.); 5,327,778 (Park); and 5,365,776 (Lehmann et al.).
The following U. S. patents disclose viscosity or flow measuring devices, or liquid level detecting devices using optical monitoring: U.S. Patent Nos. 3,908,441 (Virloget); 5,099,698 (Kath, et. al.); 5,333,497 (Br nd Dag A. et al.). The Virloget'441 patent discloses a device for use in viscometer that detects the level of a liquid in a transparent tube using photodetection.
The Kath'698 patent discloses an apparatus for optically scanning a rotameter flow gauge and determining the position of a float therein. The Br nd Dag A. '497 patent discloses a method and apparatus for continuous measurement of liquid flow velocity of two risers by a charge coupled device (CCD) sensor.
U.S. Patent No. 5,421,328 (Bedingham) discloses an intravascular blood parameter sensing system.
A statutory invention registration, H93 (Matta et al.) discloses an apparatus and method for measuring elongational viscosity of a test fluid using a movie or video camera to monitor a drop of the fluid under test.
The following publications discuss red blood cell deformability and/or devices used for determining such: Measurement of Human Red Blood Cell Deformabilitv Using a Single Micropore on a Thin Si3N, Film, by Ogura et al, IEEE Transactions on Biomedical Engineering, Vol. 38, No. 8, August 1991; the Pall BPF4 High Efficiency Leukocyte Removal Blood Processing Filter S sue, Pall Biomedical Products Corporation, 1993.
Notwithstanding the existence of the foregoing technology, a need remains for an apparatus and methods for use in screening a pharmaceutical or other compound to determine its effect or efficacy in altering, e.g., lowering, the viscosity of the blood of a living being, in altering the deformability of the red blood cells in the blood of a living being, and in altering the thixotropic properties of the blood of a living being.
OBJECTS OF THE INVENTION
Accordingly, it is the general object of the instant invention to provide an apparatus and methods of use for meeting those needs.

It is a further object of this invention to provide in vivo apparatus and methods of use for determining the viscosity of the blood of a living being in order to evaluate the efficacy of a pharmaceutical to alter the viscosity of the blood of a living being.
It is a further object of this invention to provide in vivo apparatus and methods of use for determining the deformability of the red blood cells in the blood of a living being in order to evaluate the efficacy of a pharmaceutical to alter the deformability ofthe red blood cell of a living being.
It is still a further object ofthis invention to provide in vivo apparatus and methods ofuse for determining the thixotropic properties of the blood of a living being in order to evaluate the efficacy of a pharmaceutical to alter the thixotropic properties of the blood of a living being.
SUMMARY OF THE INVENTION
These and other objects of this invention are achieved by providing apparatus and methods for method of screening a pharmaceutical to determine its efficacy in altering the viscosity of the blood of a living being. The apparatus comprises an in-vivo instrument arranged to be coupled to the blood flowing within the vascular system of a living being.
In accordance with one aspect of this invention the method comprises the step of introducing a pharmaceutical (or other compound) into the body of a living being, and utilizing the in-vivo instrument to determine the likely effect of the introduced pharmaceutical on the viscosity of a living being's blood.
In accordance with another aspect of this invention the method comprises the step of introducing a pharmaceutical (or other compound) into the body of a living being, and utilizing the in-vivo instrument to determine the likely effect of the introduced pharmaceutical on the deformability of the red blood cells of a living being's blood.
In accordance with still another aspect of this invention the method comprises the step of introducing a pharmaceutical (or other compound) into the body of a living being, and utilizing the in-vivo instrument to determine the likely effect of the introduced pharmaceutical on the thixotropic properties of a living being's blood.
DESCRIPTION OF THE DRAWINGS
Other objects and many of the intended advantages of this invention will be readily appreciated when the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings wherein:

WO 99!66839 PCT/US99/13943

6 Figs. lA and 1B form an illustration and functional diagram of one embodiment of a system for in-vivo measuring the viscosity of the blood of a human being;
Fig. 2A is an isometric view of a portion of the system shown in Fig. 1, namely, a portion of blood receiving means and monitoring means;
Fig. 2B is an isometric view of another portion of the system shown in Fig. 1, namely, an exemplary test station;
Fig. 3 is an illustration of the construction and function of the blood receiving means;
Fig. 4 is a graph of a parameter measured by the system if Fig. 1, namely, the "head" of the column of fluid plotted versus time;
Figs. SA-SG are illustrations of a portion of the system shown in Fig. 1 showing the operational sequence thereof;
Fig. 6 is an enlarged isometric view of a portion of the system, namely, a capillary tube;
Fig. 7 is a view similar to Fig. 6, but showing an alternative embodiment of the capillary tube;
Fig. 8A is a view similar to Fig. 6 and 7, but showing an alternative embodiment of the capillary tube;
Fig. 8B is a greatly enlarged cross-sectional view taken along line 8B-8B of Fig. 8A;
Fig 9 is an enlarged cross-sectional view of yet another alternative embodiment of the capillary tube;
Fig. 10 is an enlarged sectional view through a portion of the components shown in Fig.
3 to include means, e.g., a buffer piston at the blood/transmission fluid interface to isolate the blood of the being from the transmission fluid used by the system;
Fig. 11 is a block diagram of a portion of the system shown in Fig. i, namely, the sensor means;
Fig. 12 is an enlarged cross-sectional view of the sensor means taken along line 12-12 of Fig. 2A;
Fig. 13 is an illustration of a calibration test rig for use with the system of Fig. 1; and Fig. 14 is a graph similar to Fig. 4 showing the head of the column of fluid plotted versus time to show a thixotropic characteristic of the blood.

7 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring now in greater detail to the various figures of the drawing, wherein like reference characters refer to like parts, there is shown in Figs. IA and 1B at 20 a liquid viscosity measuring system constructed in accordance with the present invention. The system 20 has particular utility for measuring in-vivo the viscosity of the blood of a living being.
Although the apparatus 20 has many applications, the preferred embodiment of the apparatus 20 is used to measure the viscosity of the blood anywhere in a patient's vascular system, e.g., veins, arteries, pulmonary system, left atrium, left ventricle, etc.
It should be understood that blood is a non-Newtonian fluid. A Newtonian fluid may be defined as one in which the viscosity does not vary with the rate of shear within the non-turbulent flow range, whereas a non-Newtonian fluid, such as blood, exhibits a viscosity that is variable with the rate of shear in the non-turbulent flow range. As a result, when the viscosity of a non-Newtonian fluid is plotted as a function of rate of shear, a curve is produced, instead of a straight line. Therefore, to obtain an accurate determination of blood viscosity, it is necessary to obtain a viscosity measurement over a range of shears.
The concept of the present invention is to monitor, on a substantially continuous basis, the rising head of an externally located column of fluid coupled to a portion of the patient's body in which the blood flows, thus, effectively monitoring the patient's blood in-vivo. The data from this rising head is used to calculate the viscosity of the blood at a large multiplicity of points during the rise of the column for various different flow rates, thereby providing a viscosity of the blood over a range of shears. The monitoring of the rising column solves the problem of how to generate a range of shears necessary to obtain an accurate measurement of the blood viscosity.
As shown in Figs. lA and 1B, the apparatus 20 basically comprises a blood sampling means 22 and a calculation means 24 that are coupled together to provide the viscosity measurement. The blood sampling means 22 comprises a catheter 26, which in a preferred embodiment comprises a capillary tube. The catheter 26 has an inside diameter D, and a length, Ll. The catheter 26 is introduced into the body 28 of the being (patient) to an internal situs 30 (e.g., a vein, artery, etc.) to enable blood 31 to flow into the catheter 26.
Thus, the catheter 26 serves as a blood receiving means. The catheter 26 is connected via a hub 32 to a conduit means 34 having a inside diameter DZ. A first valve means 36 (e.g., a 3-way valve) selectively couples an injector means 38 to the conduit means 34. The injector means 38 comprises a reservoir 40

8 for containing an indicator or transmission fluid 41 {e.g., a liquid such as saline solution, alcohol, or any sterile water-type liquid) which, when injected into the conduit means 34, forms a column of fluid 42 (to be discussed later) that can be monitored (e.g., optically monitored-an optimum dye can be used for coloring the transmission fluid for maximizing readability by an optical sensor). The other end of the conduit means 34 is coupled to a riser tube 44.
The hollow interior of the riser tube 44 forms a lumen that permits the column of fluid 42 level to be detected as a function of time. The riser tube 44 has an inside diameter of D3. The upper end of the riser tube 44 comprises a second valve means 46 (e.g., a 2-way valve) that vents the riser tube 44 to atmosphere when the valve 46 is opened. The first valve means 36 and second valve means 46 preferably include hydrophobic vents (not shown) to eliminate blood spillage.
It should be understood that optimum selection of the tube sizes for the capillary tube 26, the conduit means 34 and the riser tube 44 minimizes the effects of viscosity and surface tension of the transmission fluid 41. It should also be understood that it is preferable to have the capillary tube 26 fully inserted into the vascular system, i.e., the capillary tube 26 is inserted such that a continuation of the conduit means 34 of diameter DZ is also disposed in the vascular system.
The column of fluid 42 is monitored by monitoring means 48. The monitoring means 48 comprises a sensor means 50 (e.g., a charge-coupled device, CCD, including associated electronics, Fig. 11 and an associated power supply 51 ) coupled to a microprocessor means 52 (e.g., a personal computer) which further comprises appropriate diagnostic software 54. The monitoring means 48 monitors the height of the column of fluid 42 as it rises throughout the length of the riser tube 44 during the test or run to determine the patient's blood viscosity.
Peripheral indicator means 56, e.g., a visual display 58, a counter means 60, a printer 62, provides data and/or graphics pertaining to the viscosity/shear rate measurements. In addition, a modem 64 can be connected to the monitoring means 48 to provide all pertinent data to some remote location, e.g., via the Internet or World Wide Web 66.
In accordance with a preferred aspect of this invention, the visual display 58 and/or printer 62 serve to present graphical representations of measured parameters such as viscosity vs. shear, or viscosity vs. height of column of fluid ("head"), or diagnoses.
The counter means 60 is used to numerically display such items as viscosity at a particular shear and/or the head at which the velocity of the column of fluid is zero, e.g., the thixotropic point {to be discussed

9 PCTNS99/13943 later). The viscosity/shear rate data can be stored in the microprocessor means 52 and can be compared with databases 54 (on associated CD-ROM, diskette or PC cards) to present possible diagnoses to the physician.
Fig. 2A depicts one portion of the implementation of the system 20. As shown, the injector means 38, a portion of the conduit means 34, the first valve means 36, the riser 44, and the second valve means 46 are mounted on a support plate 68 to form a tubing assembly 69. The tubing assembly 69 is configured to be removably mounted inside a housing 70 which contains the sensor means 50 and the power supply 51. The support plate 68 is mounted in the housing 70 with the appropriate connections in order to position the riser tube 44 vertically and directly opposite the sensor means 50 for proper monitoring. In addition, during insertion of the tubing assembly 69, the appropriate valve control connections 72 are made so that the first valve means 36 and second valve means 46 can be properly controlled automatically in sequence. Location pins 73 and location holes 75 are provided to ensure that the support plate 68 is properly aligned, thereby disposing the riser tube 44 directly opposite the sensor means S0. The support plate 68 comprises a transparent material that permits the sensor means 50 to optically monitor the column of fluid 42. It should be understood that the injector means 38 is pre-charged with the transmission fluid 41 which is held captive in the reservoir 40 by the 3-way valve 36. Only when the valve 36 is properly oriented, does the transmission fluid 41 flow out of the injector means 38 and into the conduit means 34.
Once the tubing assembly 69 is secured in the housing 70, a door 74 can be releasably secured to create a sufficiently dark environment to support proper column illumination 76 and level detection by the sensor means 50 during the run. Once a viscosity measurement procedure or run is completed, the tubing assembly 69 is removed, disconnected from the capillary tube 26, and then discarded. To run another test, a new tubing assembly 69 is connected to the capillary tube 26 and re-installed into the housing 70.
It should be understood that it is within the broadest scope of this invention that the first 36 and second valve means 46 can be controlled manually, i.e., proper operation ofthe apparatus 20 does not require automatic control of the first 36 and second valve means 46.
An exemplary test station is shown in Fig. 2B. It should be understood that although the apparatus 20 is shown with the capillary 26 inserted into a patient's arm, the apparatus 20 is not limited in use with that portion of the patient's body. Other station configurations could be used where the capillary 26 is inserted into other portions of the patient's body for blood to flow into the capillary tube 26. With the test station shown in Fig. 2B, the patient 78 is seated with his/her arm disposed on a horizontal surface 80. The capillary 26 is inserted percutaneously into the patient's arm until its distal end, and preferably its entire length Ll, is within a desired vessel, e.g., a vein. The conduit means 34 couples the capillary 26 to the housing 70. The housing 70 is releasably disposed on a fixed vertical surface 82. The vertical surface 82 comprises adjustment means 84 that permit the entire housing 70 to be manually displaced in a vertical direction and then releasably secured at any desired vertical height. The important point is that the operator can change the relative vertical position of the housing 70 with respect to the vertical position of the portion of the patient in which the capillary tube 26 has been inserted for reasons to be understood later. The microprocessor means 52, visual display 58 and printer 62 are also shown at the station.
Fig. 3 is a functional diagram of the apparatus 20. With respect to Fig. 3, the basic operation of the apparatus 20 is shown in Fig. 3. As blood 31 flows into and through the capillary tube 26 and into the conduit means 34, the blood 31 encounters the transmission fluid 41 and displaces the transmission fluid 41 up into the riser tube 44, thereby forming the column of fluid 42. The sensor means 50 (e.g., a CCD array) monitors the rise of the column of fluid 42 in real time by detecting the interface between the top of the column of transmission fluid 42 and the gas (e.g., air) in the riser tube above the fluid. This optical interface (e.g., meniscus) is readily detectable by the sensor means S0. Operation of the first valve means 36 and second valve means 46 are discussed below.
If the following assumptions are made, in particular, D1 is much less than D2; and D, is much less than D3 then it can be shown that the viscosity (rl, (t)) and the shear rate (y~(t)) of the blood in the capillary tube 26 are given by:

,O1(t) - ( P.,gtDl2).

ln( hm _h(t) ) 2 __P,3~ 2 y~(t) = 8D3 (h~,( ~ )e A ),where A = 32t~~(t)L~Da where r),(t) represents the viscosity;
y,(t) represents the shear rate;
pe represents the density of the transmission or indicator fluid;
g represents the gravitational constant;
t represents the time of measurement, D, represents the inside diameter of the capillary tube;
Ll represents the length of the capillary tube;
D3 represents the inside diameter of the column of transmission or indicator fluid;
hW represents the final height of the column of transmission or indicator fluid; and h(t) represents the instantaneous height of the column of transmission or indicator fluid.
The viscosity, rl1(t), of the blood is thus graphically represented as shown in Fig. 4. To increase the range of shears, a longer capillary tube 26 can be used (i.e., increase Ll).
Operation of the apparatus 20 is depicted in Figs. SA-SH and is as follows:
The portion of the patient's vascular system (e.g., vein, artery, etc.) into which the capillary tube 26 is to be inserted is disposed on the horizontal surface 80.
This entry point on the patient becomes the "DATUM" reference and it represents a vertical height reference.
Figs. SA-SB: A guidewire 86 is introduced into the vascular system of the patient via a piercer 88. The piercer 88 is removed, leaving the guidewire 86 in place.
The following steps are preferably automated so that once the capillary tube 26 is inserted in the patient, the operator need only activate a switch (not shown) of a controller (also not shown) that would automatically carry out the following steps:
Fig. SC: First valve means 36 is opened so that ports A and B are in communication while ports A to C and B to C are closed; the second valve means 46 is closed. The capillary 26 is then flushed.

Fig. SD: First valve means 36 is totally closed and the capillary 26 is threaded over the guidewire 86 and then disposed into the patient's vascular system. The DATUM
level is established for the capillary tube 26 and the riser tube 44. A DATUM mark is made on the fixed vertical surface 82.
Fig. SE: The guidewire 86 is removed and the DATUM level is established for the capillary tube 26 and the riser tube 44. A "0" mark is created on the riser tube 44 that is aligned with the DATUM level.
Fig. SF: First valve means 36 is moved to open communication between ports A
and C
and second valve means 46 is moved to open communication between ports D and E. The operator then depresses the plunger 90 on the injection means 38 to fill the riser tube 44 with transmission or indicator fluid up to the "0" or DATUM mark. Both the first valve means 36 and the second valve means 46 are then closed.
Fig. SF: Permit blood pressure to pressurize the column of fluid 42. The operator opens the first valve means 36 so that ports B and C are in communication, thereby permitting blood to flow (approximately O. Scc of blood) into conduit means 34. The column of fluid 42 will rise from the 0 mark to a new level. The operator then manually displaces the housing 70 downward until the new level is aligned with the DATUM mark on the fixed vertical surface 82. This action permits the determination of blood's (e.g., the venous) static pressure using the closed-offriser tube 44 as a "barometer."
Fig. SG: To avoid overflowing the riser tube 44 during the run, it is necessary to calculate the approximate final level or head, h~, of the column of fluid 42 and to lower the housing 70 by that amount. Boyle's Law is used to estimate the likely rise ho, of the column of fluid 42 in step SF. The housing 70 is then dropped by the amount h~. The housing 70 is then secured at that height to prepare the sensor means 50 to monitor the rise of the column of fluid 42. The second valve means 46 is then opened and the column of fluid 42 begins to rise.
If the test is to be run again, the tubing assembly 69 is discarded and a new tubing assembly 69 installed in the housing. If the transmission fluid 41 in the injector means 38 is of a biocompatible material, a portion of the transmission fluid 41 can be used to flush the apparatus 20, all the way to the tip of the capillary tube 26, as shown in Fig. SC.
Before a viscosity measuring run is made and as part of the automated procedure discussed above, a current barometric pressure reading is obtained (e.g., from a barometer not shown, internal to the calculation means 24) and is provided to the microprocessor means 52.
Thus, the apparatus 20 calculates the proper viscosity/shear rate plot based on the existing current atmospheric pressure. In addition, vents may be provided throughout the apparatus 20 to minimize the erect on computed viscosity accuracy.
It should be understood that the process described above could also be accomplished with the use of a hemostasis valve (e.g., a "Heparin Lock") between the capillary tube 26 and the conduit means 34. This allows the capillary tube 26 to be left in place when a plurality of runs are to be made. Furthermore, a hemostasis valve having a "Y" fitting could be disposed close to the point where the capillary tube 28 enters the vessel in order to permit the passage of a the guide wire 86 after the apparatus 20 is flushed without getting air bubbles.
The capillary tube 26 should constructed of, or coated with, a material or materials that prevent the blood 31 from adhering to the capillary tube's internal walls, e.g., an anti-thrombogenic material, such as Heparin, and/or anti-thrombolytic coatings, e.g., phosphoryl choline, etc., can be used to minimize blood clotting. Phosphoryl choline compounds are available from Biocompatibles, Ltd., Uxbridge, UK. Such a construction or coatings facilitate the long-term placement of the capillary tube 26 within the vascular system of the patient.
Furthermore, as shown most clearly in Fig. 6, the tip of the capillary tube 26 preferably comprises a plurality of ports 92. This ensures that if the tip of the capillary tube 26 abuts any portion of the interior of the vessel wall once inserted into the patient's vascular system, blood flow entry 94 into the capillary tube 26 will not be obstructed or impeded.
An alternative embodiment of the capillary tube 26 is shown in Fig. 7 and includes an intravascular capillary with a controlled lumen or resistor for the viscometer function and with another for measuring pressure. For example, the capillary tube 126 comprises a first lumen 96 for transmitting the blood 31 as discussed previously and comprises a second lumen 98 that is coupled to a pressure transducer (not shown) that is coupled to the calculation means 24. Thus, the second lumen 98 provides a continuous reference of the patient's blood pressure to the calculation means 24. Unlike the process described earlier, whereby the operator determines the patient's blood pressure before the test is run, using this second lumen 98, the calculation means 24 is provided with a continuous blood pressure reference throughout the run.
In some patients, the actual blood pressure may change during the run. Such blood pressure variations or pulsations need to be accounted for in determining the proper viscosity/shear versus time curve.

Having a continuous blood pressure reference can thus be compensated for during the blood viscosity/shear determination.
Another alternative embodiment of the capillary tube 26 is shown in Figs. 8A-8B and 9.
This embodiment includes an intravascular capillary with a controlled lumen or tube with alternative resistive members, such as a number of small capillary tubes in a bundle (Figs. 8A-8B). Alternatively, the tube is filled with very small spheres (Fig. 9), or a sintered column (not shown). With respect to the embodiment as shown in Figs. 8A-8B, the capillary tube 226 comprises a plurality of small capillaries 100, each having different internal diameters (di, dz, d3, etc.). Use of the plurality of small capillaries not only permits the length L, to be smaller but also permits the attainment of very small shears. Where these diameters are less than the average diameters of a typical red blood cell, the system 20 can be used to determine the blood pressure at which blood flow starts. This action provides an indication of the deformability of the being's red blood cells since those cells will have to deform to pass through the small capillaries 100.
in the alternative embodiment of the capillary tube shown in Fig. 9, the capillary tube 326 includes very small spheres 102 within it to create interstices which are smaller than the average diameter of a red blood cell, so that such cells will have to deform to pass therethrough.
To eliminate or at least minimize the possible miscibility/contamination problem between the transmission fluid/blood interface in the conduit means 34, a buffer piston as shown in Fig.
may be used. That piston can be of any suitable construction, e.g., a carbon slug to isolate the blood 31 from the transmission fluid 41 at their interface. In particular, the piston 104, having a specific gravity of approximately 1.0, transmits the motion or flow of the blood 31 down the capillary tube to the transmission fluid 41 while isolating or separating these two fluids from each other. Alternatively, although not shown, a buffer fluid could be introduced at the interface between the blood 31 and the transmission fluid 41 to reduce any miscibility/contamination problems.
Fig. 11 is a block diagram of the sensor means 50, while Fig. 12 shows its construction, i.e., a cross-sectional view of it taken along line 12-12 of Fig. 2A but with the support plate 68 already secured to the housing 70. Thus, as can be seen, an exemplary implementation of the sensor means 50 comprises a linear array of illuminators 76 (see Figs. 2A and 12), rod lenses 106, and sensor chips 108 mounted on a PCB substrate 110. One particularly useful commercial IS
Jose, CA. The sensor means 50 includes a glass cover 112 that abuts the riser tube 44 when the support 68 is installed, as described earlier. An integrated lens 114 may be disposed on the opposite side of the glass cover 112 to improve viewing by the rod lens 106.
In order for the system 20 to operate properly, it is necessary for the calculation means 24 to take into account the fluid resistance of the tubing assembly 69 that is mounted in the housing 70. To accomplish that a test rig is utilized. Fig. 13 depicts an exemplary test rig 116 for the tubing assembly 69 of the system 20. A bar code 118 is provided on the support plate 68 (Figs. 2A and 13) that contains a calibration factor for that particular tubing assembly 69.
Thus, just before a viscosity run is made, an automatic scanner 119, coupled to the PC 52, scans the bar code 118 and loads the PC 52 with the particular calibration factor.
To determine the calibration factor, the tubing assembly under calibration, Ai, is coupled to the test rig 116, as shown in Fig. 13. An air supply 120 delivers clean dry air at a predetermined pressure, PA$ (e.g., 100 psi) that can be regulated (via a regulator REG) down to 30in HzO. The air supply I20 delivers the flow through a calibrated orifice, Al, having a known resistance. The input ofthe tubing assembly under test A, is coupled to the output ofAl and the output of the tubing assembly under test AZ is vented to atmosphere. When the air supply 120 delivers the air flow, depending on the internal fluid resistance of the tubing assembly under test AZ, a pressure, PTA, appears at the input of the tubing assembly under test, A2. A pair of open-ended manometers 122A and 122B are coupled to the input of A1 and the output of A,, respectively, to monitor PAS and PTA, respectively. The ratio PAS/PTA
represents the calibration factor. This calibration factor is then encoded into the bar code 118. Thus, each time a tubing assembly 69 is mounted in the housing 70 and the bar code 118 read into the PC
52, the calculation means 24 can make a viscosity determination based on the specific fluid resistance of that mounted tubing assembly 69.
In accordance with another aspect of the present invention and to minimize measurement errors, the system 20 includes the means for controlling the formation of a meniscus 124 (Fig.
3) at the top of the column of transmission fluid 42. In particular, coatings for the riser tube 44 can be introduced to control the surface tension precisely by providing controlled surface energy, thus flattening the meniscus 124. This meniscus 124 can be further controlled by changing the molecular make-up of the riser tube 44, the transmission fluid 41 being used and the gas above the column of fluid 42. Furthermore, to make the surface energy repeatable and predictable, the inner surfaces of riser tube 44 maybe coated by vapor deposition with surfactants, e.g., silicone.
By including suitable surfactants, such as silicone, in the extrusions the surfactants migrate to the surfaces in a predictable manner.
Another embodiment (not shown) of the apparatus 20 includes a riser tube 44 that is inclined to increase the sensitivity. In particular, if the riser tube 44 were angled away from a vertical orientation, for each millimeter rise in vertical height of the column of fluid 42, there will be more than one millimeter of displacement of the column of fluid 42 in the riser tube 44.
In accordance with another aspect of the subject invention means 124 (Fig. 2B
can be provided to apply vibratory energy to the patient to determine its effect on the patient's blood viscosity and the data developed can then be used to provide customized vibratory therapy to provide beneficial effects. In particular, that aspect of the invention makes use of a vibration source 124 that generates vibratory energy whose amplitude and frequency can be controlled by the operator. This vibratory energy is applied either before or during a viscosity measuring run.
Although the vibratory energy is shown in Fig. 2B as being applied to the patient's arm only, it is within the broadest scope of the invention that the vibratory energy can be applied to all or only a portion of the patient's body. The vibration may also be applied to the column of fluid 42, and/or to the capillary tube 26, to obtain a smoother flow of fluid.
Another significant feature of the system 20 is its ability to monitor the level of the column of fluid 42 at which the velocity becomes zero, i.e., the thixotropic point of the blood flow. The thixotropic point represents a shear stress being supported at zero velocity, as graphically depicted in Fig. 14. Presentation of the shear or head at which flow restarts after a set time at zero motion provides an indication of the clotting characteristic of the patient.
It should be understood that the diagnostic software 54 allows for the dynamic effects of deceleration of the column of fluid 42 and for the viscous effects of the various diameters of tubing as the blood 31 and the transmission fluid 41 pass through the system 20.
It should be understood that another implementation of the system 20 comprises a molded or etched channel system as a substitute for the tubing discussed above.
As mentioned earlier, the apparatus 20 has other applications, such as viscosity measurements of other flowable material, e.g., oils, paints and cosmetics.
The in-vivo apparatus of the subject invention can be used to screen or test one or more pharmaceuticals or other compounds to determine its(their) likely effect on one or more parameters of a living being's blood. For example, the apparatus can be used to determine in-vivo viscosity of a living being's blood to screen a pharmaceutical or other compound in a test subject, e.g., a living laboratory animal or human being, in order to predict the likely effect in altering, e.g., efficacy in lowering, the viscosity of the blood of a living, e.g., human, being to whom the pharmaceutical will ultimately be administered. The system can be used for determining the deformability of the red blood cells of a living to screen the effect of the pharmaceutical or other compound in the test subject, in order to predict its likely effect on the deformability ofthe red blood cells ofthe living being to whom the pharmaceutical will ultimately be administered. So too, the system can be used for determining the thixotropic properties of the blood of a living to screen the effect of the pharmaceutical or other compound in the test subject, in order to predict its likely effect on the thixotropic properties ofthe blood ofthe being to whom the pharmaceutical will ultimately be administered.
Without further elaboration, the foregoing will so fully illustrate our invention and others may, by applying current or future knowledge, readily adapt the same for use under various conditions of service.

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Relation between the cases US Date and Number PCT PCT Publn 1997 Aug 28 (91990fi)1998 Aug 26 ) 1999 Mar 4 ) 1997 Nov 7 966076 PCT/US/98/17657 W099/10724 1998 June 23 (103232)1999 June 22 ) 1999 Dec 29 So, for case (2) - case 1 is an intermediate publication if we hold the priority date.

Claims

1. A method of screening a pharmaceutical to determine its efficacy in altering the viscosity of the circulating blood of a living being, characterised by the steps of:
(a) introducing the pharmaceutical into the body of the living being;
(b) passing the circulating blood (30) of the living being through a lumen of known dimensions into contact with a second fluid (42) in an elongate container (44) whereby the length of the fluid changes as a result of the contact;
(c) generating a signal by signal generating means (50) according to movement of the length;
(d) calculating the viscosity of the circulating blood from the generated signals using calculating means (52); and (e) determining the likely effect of said pharmaceutical on the viscosity of the circulating blood of the living being from the calculated viscosity.

2. The method of Claim 1 wherein said step of determining the likely effect of said pharmaceutical comprises determining the pharmaceutical's efficacy in lowering the viscosity of the circulating blood of the living being.

3. A method according to Claim 1, wherein said living being to which said pharmaceutical is to be administered is a human being.

4. A method according to Claim 1, wherein said living being is an animal.

5. The method according to any preceding claim, wherein said step of passing the circulating blood (30) of the living being through a lumen comprises passing the circulating blood through a capillary tube having a known length (L1) and diameter (D1).

19 Cancel Claim 6.

7. A method of screening a pharmaceutical to determine its efficacy in altering the deformability of red blood cells in the circulating blood of a living being, characterised by the steps of:
(a) introducing the pharmaceutical into the body of the living being;
(b) passing the circulating blood (30) of the living being through blood flow restricting means of known dimensions;
(c) monitoring the passage of the circulating blood through said blood flow restricting means;
(d) determining the likely effect of said pharmaceutical on the deformability of the red blood cells of the circulating blood of the living being from the monitored passage of the circulating blood through said blood flow restricting means.

8. A method according to Claim 7, wherein said living being to which said pharmaceutical is to be administered is a human being.

9. A method according to Claim 7, wherein said living being is an animal.

10. The method of Claim 7 wherein said blood flow restricting means comprises a capillary tube of a known length (L1) and diameter (D1) and having a longitudinal axis and further comprising a plurality of smaller capillary tubes of varying diameters, said varying diameters being smaller than said diameter (D1), and wherein each of said smaller capillary tubes is aligned with said longitudinal axis.

11. The method of Claim 7 wherein said blood flow restricting means comprises a capillary tube of a known length (L1) and diameter (D1) and further comprising a plurality of spheres disposed within said capillary tube to create interstices which are smaller than the average diameter of a red blood cell.

12. A method for screening a pharmaceutical to determine its efficacy in altering the thixotropic properties of the circulating blood of a living being, characterised by the steps of:
(a) introducing the pharmaceutical into the body of the living being;
(b) passing the circulating blood (30) of the living being through a lumen of known dimensions into contact with a second fluid (42) in an elongate container (44) whereby the length of the fluid changes as a result of the contact;
(c) monitoring the deceleration in the movement of the length of the fluid until the fluid reaches a stopped position corresponding to the stopped movement of the circulating blood in the lumen;
(d) causing the circulating blood in the lumen to begin moving again and monitoring the corresponding movement of the fluid from the stopped position;
and (e) determining the likely effect of said pharmaceutical on the thixotropic properties of the circulating blood of the living being from the monitored deceleration and corresponding movement of the fluid.

13. A method according to Claim 12, wherein said living being to which said pharmaceutical is to be administered is a human being.

14. A method according to Claim 12, wherein said living being is an animal.

Cancel Claim 15 and 16.