WO2017184954A1 - Blood separation system - Google Patents

Blood separation system Download PDF

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Publication number
WO2017184954A1
WO2017184954A1 PCT/US2017/028793 US2017028793W WO2017184954A1 WO 2017184954 A1 WO2017184954 A1 WO 2017184954A1 US 2017028793 W US2017028793 W US 2017028793W WO 2017184954 A1 WO2017184954 A1 WO 2017184954A1
Authority
WO
WIPO (PCT)
Prior art keywords
container
pump
configured
blood
separation device
Prior art date
Application number
PCT/US2017/028793
Other languages
French (fr)
Inventor
Nichols RICHARDSON
Yinting CHU
Original Assignee
StemBios Technologies, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US201662326168P priority Critical
Priority to US62/326,168 priority
Application filed by StemBios Technologies, Inc. filed Critical StemBios Technologies, Inc.
Publication of WO2017184954A1 publication Critical patent/WO2017184954A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3693Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits using separation based on different densities of components, e.g. centrifuging
    • A61M1/3695Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits using separation based on different densities of components, e.g. centrifuging with sedimentation by gravity
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483Physical analysis of biological material
    • G01N33/487Physical analysis of biological material of liquid biological material
    • G01N33/49Blood
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00Special media to be introduced, removed or treated
    • A61M2202/04Liquids
    • A61M2202/0413Blood
    • A61M2202/0429Red blood cells; Erythrocytes
    • A61M2202/0437Blood stem cells

Abstract

A separation system comprising a blood separation device containing a controller, a red-blood-cell (RBC) detection module, and a pump driver; and a cartridge configured to be reversibly attached to the blood separation device, the cartridge including: (i) a first container configured to contain a blood sample, wherein the first container includes a first opening; (ii) a tubing in fluid flow communication with the first opening; (iii) a pump in fluid flow communication with the tubing, wherein the pump is configured to move a fluid from the first container to the pump and to contain a fluid; and (iv) a check valve mounted to the tubing, wherein the check valve is configured to allow a fluid to flow from the first container to the pump and to not allow a fluid to flow from the pump to the first container.

Description

BLOOD SEPARATION SYSTEM

BACKGROUND

Stem cells have the ability to self-renew to generate more stem cells and also to become almost any type of specialized cells. Stem cell research is useful for learning about human development and is one of the most fascinating areas of contemporary biology.

Therefore, stem cells offer exciting promise for future medical science.

SUMMARY

In one aspect, described herein in a separation system, comprising a blood separation device containing a controller, a red-blood-cell (RBC) detection module, and a pump driver; and a cartridge configured to be reversibly attached to the blood separation device. The cartridge including: (i) a first container configured to contain a blood sample, wherein the first container includes a first opening; (ii) a tubing in fluid flow communication with the first opening; (iii) a pump in fluid flow communication with the tubing, wherein the pump is configured to move a fluid from the first container to the pump and to contain a fluid; and (iv) a check valve mounted to the tubing, wherein the check valve is configured to allow a fluid to flow from the first container to the pump and to not allow a fluid to flow from the pump to the first container. In one embodiment, the RBC detection module is configured to (i) detect red blood cells in the tubing at a detection point positioned between the first opening and the pump, and (ii) generate a first signal to be transmitted to the controller when red blood cells are detected in the tubing. The RBC detection module can be configured to emit a light to the detection point and to detect reflection, scattering, absorption or fluorescence of the light that specifically indicates the presence of red blood cells in the fluid.

The controller can be configured to receive the first signal from the RBC detection module, and after receiving the first signal, generate a second signal to be transmitted to the pump driver. The pump driver can be configured to receive the second signal, and after receiving the second signal, drive the pump to stop moving a fluid from the first container to the pump. The blood separation device can further includes a temperature sensor configured to detect a temperature of a fluid in the first container and to generate a third signal to be transmitted to the controller when the temperature is detected. The blood separation device can further include a cooling driver coupled to the controller, and wherein the controller is configured to, after receiving the third signal, generate and transmit a fourth signal to the cooling driver. The cooling driver can be configured to receive the fourth signal, and after receiving the fourth signal, drive the cooling module to modulate the temperature of a fluid in the first container. The separation device can further include a holder configured to press the first container against the cooling module. The separation device can also include a heatsink 5 adapted to transfer heat from the cooling module to the ambient of the blood separation

device. In one embodiment, the separation device is configured to communicate with a central control unit via wireless communication. Further, the separation device can be configured to reversibly lock the cartridge in the separation device.

In one embodiment, the cartridge further includes a second container in fluid flow o communication with the pump, wherein the pump is adapted to move a fluid from the pump to the second container. The pump driver can be configured to, after receiving a driving signal from the controller, drive the pump to move a fluid from the pump to the second container. The cartridge is adapted to, when fitted in the blood separation device, allow separation of a blood sample in the first container into an upper layer and a lower layer by 5 gravity. The pump and the second container can be both configured to be reversibly attached to the cartridge.

In another aspect, a method of separating a blood sample is described herein. For example, the method can include use of the separation system described in this disclosure. In one embodiment, the method includes providing a cartridge including (i) a first container that o contains a blood sample mixed with a divalent cation chelating anticoagulant, wherein the first container includes a first opening; (ii) a tubing in fluid flow communication with the first opening; (iii) a pump in fluid flow communication with the tubing, wherein the pump is reversibly attached to the cartridge and is configured to move a fluid from the first container to the pump and to hold a fluid; and (iv) a check valve mounted to the tubing, wherein the 5 check valve is configured to allow a fluid to flow from the first container to the pump and to not allow a fluid to flow from the pump to the first container, wherein the cartridge is configured to be reversibly attached to a blood separation device; attaching the cartridge to the blood separation device such that the first container is in an upright position and the first opening is at the top of the container; cooling the blood sample in the first container to 2°C 0 and 12°C; maintaining the blood sample at 2°C and 12°C for 6 to 72 hours, whereby the blood sample separates into an upper layer and a lower layer by gravity; and pumping a portion of the upper layer out of the first container to the pump through the first opening and the tubing until red blood cells are detected in the tubing at a detection point positioned between the first opening and the pump, wherein the pump holds the portion of the upper layer. In one embodiment, the cartridge further includes a second container in fluid flow communication with the pump, and the method further includes a step of pumping a part of the portion of the upper layer in the pump to the second container, wherein the second container holds the part of the portion of the upper layer.

The details of one or more embodiments are set forth in the accompanying drawing and the description below. Other features, objects, and advantages of the embodiments will be apparent from the description and drawing, and from the claims.

BRIEF DESCRIPTION OF DRAWINGS

Fig. 1 is a schematic drawing showing a blood separation device having a disposable cartridge inserted therein according to an embodiment of the present disclosure.

Fig. 2 is a schematic drawing showing a blood separation device having a disposable cartridge inserted therein according to an embodiment of the present disclosure.

Fig. 3 is flow chart illustrating a red blood cell detection process according to an embodiment of the present disclosure.

Fig. 4 is a graph showing light absorption threshold levels that correspond to different states according to an embodiment of the present disclosure.

Fig. 5 is a flow chart illustrating a method of separating a blood sample derived from a subject using a blood separation system according to an embodiment of the present disclosure.

DETAILED DESCRIPTION

The present disclosure describes a separation system, which is adapted to separate a blood sample derived from a subject, such as a patient. The system includes a blood separation device capable of communicating with a central control unit (e.g., a desktop or hand-held computer) through a wireless or wired communications network, and a cartridge configured to be fitted in the blood separation device.

The size (Z) of a cell such as a somatic stem cell mentioned in all following paragraphs, of the present disclosure may be, but not limited to, described or defined as (1) the conventional definition of the size or representative length of a cell in the field of cell biology or the field of stem cells, (2) the diameter of a cell especially when the cell is substantially spherical, (3) the length of the major axis of a cell especially when the cell is substantially ellipsoidal, (4) the width of a cell when the shape of the cell has an approximate shape of a square, (5) the length of a cell when the shape of the cell has an approximate shape of a rectangle, or (6) the greatest cross-sectional or transverse dimension of a cell. The size 5 (Z), either the diameter, length, width, or greatest cross-sectional or transverse dimension, can be, but not limited to, determined or measured, for example, using an image of the cell obtained from an optical microscope or from an electron microscope such as a scanning electron microscope (SEM), or using data (e.g., two-dimensional dot, contour or density plot) of the cell obtained from a flow cytometer. The image of the cell obtained from the optical o microscope or electron microscope may be a two-dimensional (2D) cross section or three- dimensional (3D) structure of the cell. As an example, the size (Z) of the cell may be obtained by, e.g., measuring the greatest cross-sectional or transverse dimension of the cell in a 2D cross-sectional image obtained from an optical microscope or an electron microscope (e.g., SEM).

5 Somatic stem cells (also called adult stem cells) can be found in an organ or tissue such as bone marrow, fat or (peripheral) blood and possess the same basic characteristics of all stem cells. A somatic stem cell is an unspecialized or undifferentiated cell, which is capable of differentiation into specialized cell types. In the present disclosure, somatic stem cells are not embryonic stem cells; in other words, the somatic stem cells are not derived, o sourced or harvested from embryos or fetal tissue.

There are various types of somatic stem cells, including totipotent stem cells, pluripotent stem cells, multipotent stem cells, and progenitor stem cells (also called unipotent stem cells). Blastomere-like stem cells (BLSCs) are totipotent or pluripotent stem cells. Very small embryonic-like stem cells (VSELs) are pluripotent somatic stem cells. SB-1 cells 5 and SB-2 cells are pluripotent or multipotent somatic stem cells.

Referring to Fig. 1, a blood separation system includes a blood separation device 1 adapted to communicate with a central control unit (e.g., a desktop or handheld computer) through a wireless or wired communications network, and a disposable cartridge 2 configured to be fitted in the blood separation device 1. The blood separation system is capable of 0 separating a blood sample, such as a peripheral blood sample from a subject. The subject, for example, is a human (e.g., a child, teenager, adult, or elderly person) or an animal (e.g., a mammal). The blood sample contains a plurality of cells, including a small-cell portion and a large-cell portion. The small-cell portion of the blood sample contains small cells between 1 micrometer and 6 micrometers, and more preferably between 2 micrometers and 6 micrometers, in size (as defined by the above-mentioned size (Z) of a cell). The small-cell portion contains platelets, which may be less than 6 micrometers in size, and small stem cells. The small stem cells, each of which has a nucleus or nuclei, contain small somatic stem cells (which may be less than and equal to 6 micrometers in size), such as CD349(+) somatic stem cells, Lgr5(+) somatic stem cells, CD66e(+) somatic stem cells (i.e., BLSCs), and VSELs (e.g., CD133(+) somatic stem cells and CD34(+) somatic stem cells). The large-cell portion of the blood sample contains large cells greater than 6 micrometers in size (as defined by the above-mentioned size (Z) of a cell), such as large somatic stem cells greater than 6 micrometers in size and lineage cells containing red blood cells and white blood cells. After being processed, the blood sample separates into two or more separate layers including an upper layer (e.g., a supernatant liquid) and a lower layer. The upper layer of the blood sample contains the small-cell portion, and the lower layer of the blood sample contains the large-cell portion. The separation system is adapted to separate the upper layer of the blood sample from the lower layer of the blood sample.

The disposable cartridge 2, for example, can be a pre-sterilized, single-use cartridge that includes a closed system within which blood separation by gravity can be performed. Referring to Fig. 1, the disposable cartridge 2 contains: (1) a container adapted to contain the blood sample, e.g., a blood container 23 (e.g., a 50 ml, 75 ml, 100 ml, 150 ml, 200 ml, 250 ml, 300 ml, 350 ml, 400 ml, 450 ml, or 500 ml blood bag), (2) a tubing, e.g., a series or system of tubes 26a, 26b and 26c that are in fluid flow communication with the blood container 23, (3) a check valve, e.g., a check valve 27 mounted to the tubing (e.g., arranged between the tubes 26a and 26b), (4) a reversibly attached first container, e.g., a pump or syringe 24, in fluid flow communication with the tubes 26b and 26c, and (5) a reversibly attached second container, e.g., syringe 25, in fluid flow communication with the tube 26c.

The disposable cartridge 2 is adapted to be reversibly fitted to or inserted into the blood separation device 1 such that, when the disposable cartridge 2 is fitted to or inserted in the blood separation device 1, the blood container 23 is in an upright position and two openings 23 a and 23b are positioned at the top of the blood container 23. A Luer lock connector 29 used for blood collection is connected to the opening 23a of the blood container 23 so as to have the blood sample flow into the blood container 23 from the subject via the Luer lock connector 29. The tube 26a is connected to the opening 23b of the blood container 23 so as to have the upper layer of the blood sample flow into the tube 26a from the blood container 23 via the opening 23b of the blood container 23.

The check valve 27, connecting the tube 26a and the tube 26b, may be a mechanical and one-way directional valve that permits a fluid (e.g., the upper layer of the blood sample) to flow in only in a first direction (i.e. a forward direction from the blood container 23 to the first syringe 24), preventing the fluid from flowing in a second direction (i.e., a backward direction from the first syringe 24 to the blood container 23). Fluid flow in the first direction opens the check valve 27, while backflow in the second direction forces the check valve 27 closed. Therefore, the check valve 27, mounted between the tubes 26a and 26b, is adapted to have the blood sample flow in the first direction from the blood container 23 to the first syringe 24 through the tube 26a, the check valve 27 and the tube 26b in sequence and to avoid the blood sample from flowing in the second direction from the first syringe 24 to the blood container 23.

The first syringe 24 is adapted to collect and contain the upper layer of the blood sample, including the small-cell portion of the blood sample, in the blood container 23 after gravity separation. The first syringe 24 is a pump, which includes a first barrel 24a (e.g., a cylindrical tube), a first plunger 24b in the first barrel 24a, and a first opening 24c. The second syringe 25 is adapted to contain a portion of the upper layer of the blood sample flowing from the first syringe 24 via the tube 26c. The second syringe 25 includes, for example, a second barrel 25a (e.g., a cylindrical tube), a second plunger 25b fitted in the second barrel 25a, and a second opening 25c. The first syringe 24 can be adapted to contain 10% to 200% (e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, or 200%) more fluid than the second syringe 25. For example, the first syringe 24 can hold 60 ml of fluid and the second syringe 25 can hold 30 ml of fluid.

The first plunger 24b is configured to be driven by a pump driver 5 of the blood separation device 1 to move in an axial direction of the first barrel 24a of the first syringe 24 with respect to the first barrel 24a. For example, when the first plunger 24b is driven by the pump driver 5 to be pulled in the axial direction with respect to the first barrel 24a, the upper layer of the blood sample flows from the blood container 23 through the tube 26a, the check valve 27, the tube 26b, and the first opening 24c in sequence into the first barrel 24a. A hard stop 28a of the disposable cartridge 2 is adapted to prevent the first plunger 24b from coming out of the first barrel 24a in the event of malfunction of the pump driver 5. When the first plunger 24b of the first syringe 24 is driven by the pump driver 5 to be pushed in the axial direction with respect to the first barrel 24a, a portion of the upper layer of the blood sample in the first barrel 24a flows through the tube 26c and the second opening 25c into the second 5 barrel 25a of the second syringe 25. A hard stop 28b of the disposable cartridge 2 is adapted to prevent the second plunger 25b from coming out of the second barrel 25a in the event of malfunction of the pump driver 5. In summary, the first plunger 24b can be pulled and pushed inside the first barrel 24a by the pump driver 5 of the blood separation device 1, allowing the first syringe 24 to take in and expel a liquid (e.g., the upper layer of the blood o sample) through the opening 24c.

The disposable cartridge 2 further includes a divalent cation chelating-based anticoagulant preloaded in the blood container 23 to be mixed with the blood sample. The divalent cation chelating-based anticoagulant is ethylenediaminetetraacetic acid (EDTA), citrate or other calcium-chelating anticoagulant, for example. In one embodiment, the blood 5 container 23 contains an amount of the divalent cation chelating-based anticoagulant such that, after the anticoagulant is mixed with the blood sample, the blood sample contains 1.5 mg or more (e.g., 1.5 mg to 2 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, or 2 mg) of the anticoagulant per milliliter of the blood sample. In one embodiment, the disposable cartridge 2 further includes a filter 31 mounted to the tube 26a, as shown in Fig. 2. The filter 31 is o adapted to filter leukocytes from the blood sample.

Referring to Fig. 1, the blood separation device 1, which is adapted for use with the disposable cartridge 2 for separating the blood sample placed in the blood container 23 of the disposable cartridge 2, includes a controller 3, an RBC detection module 4 coupled to the controller 3, and the pump driver 5 (e.g., a pump motor or actuator) coupled to the controller 5 3. The RBC detection module 4 is adapted to detect red blood cells in the blood sample at a detection point 30 as the blood sample flows through the tube 26a, so as to generate a detection signal to be transmitted to the controller 3. The RBC detection module 4 includes, for example, a light emitting device adapted to emit a light to the tube 26a at the detection point 30 and a sensor adapted to detect reflection, scattering, absorption or fluorescence of o that light that specifically indicates the presence of red blood cells in the blood sample

flowing through the tube 26a at the detection point 30. The RBC detection module 4 may be positioned such that the flow path between the opening 23a and the detection point 30 has a distance that is less (e.g., 1 to 95%, 3%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% less) than that of the flow path between the detection point 30 and the first opening 24c. The RBC detection module 4 is adapted to perform a red-blood-cell detection when the tube 26a at the detection point 30 is 5 clear. The RBC detection module 4 is adapted to tolerate presence of bubbles, "flakes" (stray red blood cells), and a spread of the line between the upper layer of the blood sample and the lower layer of the blood sample in order to prevent premature generation of the detection signal that would end pumping prior to the complete transfer of the upper layer from the blood container 23 to the first syringe 24.

o The RBC detection module 4 can be adapted to carry out the process shown in Fig. 3.

The light emitting device can include a first light-emitting diode (LED) emitting a blue light having the wavelength of 461 nm and a second green LED emitting a green light having the wavelength of 565 nm. The sensor can include one or more photodiodes (e.g., silicon photodiodes) adapted to detect the light emitted from each LED. The RBC detection module5 4 can be adapted to perform a calibration sequence before a cartridge is fitted to the blood separation device. After receiving a calibration request (e.g., from the central control unit or the blood separation device), light levels for both the green and the blue channels are measured with the LEDs on and with the LEDs off. The current for each LED is set independently, requiring that only one light measurement is taken at a time, alternating o quickly between the blue and green LEDs. These calibration measurements are performed without the cartridge in the blood separation device. The calibration process sets the maximum bright and maximum dark levels. These levels, as well as the current being drawn by the LEDs, can be checked to determine whether they are within expected tolerance bands. Absorption levels are then scaled between these two levels for both the green and blue

5 channels. See Fig. 4.

Referring to Fig. 3, the RBC detector module has 3 output signal pins, i.e., Status 1, Status 2, and Fault. The detector also has 1 input signal pin, i.e., calibration request. If the detector passes the calibration, the output pin will indicate a "No Tube" condition, e.g., absence of the cartridge in the blood separation device. The "No Tube" condition occurs o when both the green and blue channels detect close to maximum brightness, e.g., the least amount of light absorption. The next level of absorption occurs for a "Top Layer" condition, e.g., when a portion of the upper layer from the blood container in the cartridge flows through the detection point. The green channel is better adapted at measuring this condition. If the green absorption level is below a certain level (see Fig. 4), the output pins will indicate a "Top Layer" condition. The next level of absorption occurs for an "Empty Tube" condition. This is a tube with nothing in it, or if a bubble flows through the detection point. The blue channel is better adapted at detecting this condition. If the blue absorption level is below a certain level (see Fig. 4), the output pins will indicate an "Empty Tube" condition. The last level of absorption occurs for the "Blood" condition, e.g., when red blood cells flow through the detection point. The blue channel is better adapted at measuring this condition. If the blue absorption level exceeds a certain level (see Fig. 4), the output pins will indicate a "Blood" condition.

Referring to Fig. 1, the controller 3, for example, is a microcontroller, which is a single integrated circuit chip containing a processor core, memory, and programmable input/output peripherals. The controller 3 is adapted to receive the detection signal from the RBC detection module 4, and after receiving the detection signal, generate a driving signal to be transmitted to the pump driver 5. The pump driver 5 is adapted to receive the driving signal from the controller 3, hold the first plunger 24b of the first syringe 24, and drive the first plunger 24b to move along the axial direction of the first barrel 24a with respect to the first barrel 24a. Therefore, the pump driver 5 is configured to drive a portion of the blood sample in the blood container 23 to flow through the detection point 30 positioned in the tube 26a, the check valve 27, the tube 26b, and the opening 24c, in sequence, into the first barrel

24a, based on the detection result or signal.

The blood separation device 1 further includes a cooling module 6 (e.g., a thermoelectric cooler, a vapor-compression cooler, or a liquid cooler) adapted to cool the blood sample in the blood container 23, a temperature sensor 7 coupled to the controller 3, and a cooling driver 8 (e.g., a thermoelectric driver) coupled to both the controller 3 and the cooling module 6 and adapted to drive the cooling module 6 based on a feedback from the temperature sensor 7. The temperature sensor 7 is adapted to sense a temperature associated with the blood sample in the blood container 23, such as an internal temperature of the disposable cartridge 2, so as to generate a temperature sensor signal to be transmitted to the controller 3. The controller 3 is adapted to receive the temperature sensor signal and generate a cooling signal, based on the temperature sensor signal, to be transmitted to the cooling driver 8. The cooling driver 8 is adapted to receive the cooling signal and drive the cooling module 6, after receiving the cooling signal, to cool the temperature associated with the blood sample in the blood container 23. In one embodiment, the controller 3, the cooling module 6, the temperature sensor 7, and the cooling driver 8 together are adapted to cool and maintain the temperature associated with the blood sample in the blood container 23 to a temperature between 2 degrees Celsius (°C) and 12°C, e.g., 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, irC, 12°C, 2 to 7°C, 2 to 10°C, 4 to 8°C, 4 to 12°C, or 6 to 12°C. The holder 11 of the blood separation device 1 may be used as a heat transfer mount, which is adapted to remove the heat from the blood container 23 to the cooling module 6. A passive heat exchanger 9 (e.g., a heatsink) of the blood separation device 1 is adapted to transfer the heat from the cooling module 6 to the ambient of the blood separation device 1. A fan 10 of the blood separation device 1 is adapted to remove the heat transferred to the passive heat exchanger 9 to the ambient of the blood separation device 1. In one embodiment, the holder 11 is adapted to press the blood container 23 against the cooling module 6 in order to increase the contact surface between the blood container 23 and the cooling module 6.

The holder 11 of the blood separation device 1 can be adapted to hold up the blood container 23 containing the blood sample so as to preventing it from falling down. The disposable cartridge 2 is adapted to be locked in the blood separation device 1 by a locking mechanism 12 (e.g., an electric locking mechanism) of the blood separation device 1. The locking mechanism 12 is coupled to the controller 3 and adapted to lock or unlock the disposable cartridge 2 based on a signal transmitted from the controller 3. In other words, the controller 3 is adapted to control the locking mechanism 12 to lock or unlock the disposable cartridge 2. The locking mechanism 12 may be coupled with an in-place switch or detector, which may be disposable. Alternatively, the in-place switch or detector may be integrated into the locking mechanism 12. The in-place switch or detector is adapted to confirm if the disposable cartridge 2 is properly in place inside the blood separation device 1.

Furthermore, the blood separation device 1 includes a wireless module 13 coupled to the controller 3, an identification (ID) module 14 coupled to the controller 3, a beeper 15 coupled to the controller 3, a start button 16 coupled to the controller 3, a stop button 17 coupled to the controller 3, a status displays 18 coupled to the controller 3, a liquid crystal display (LCD) 19 coupled to the controller 3, a test port 20 coupled to the controller 3, a power entry module 21, and an AC-to-DC power supply module 22 coupled to the power entry module 21. The wireless module 13 is adapted to allow wireless communication between the blood separation device 1 and the central control unit. A protocol used for the wireless communication may be a Wi-Fi protocol, such as IEEE 802.11. The identification module 14 is adapted to have a unique identifier (i.e., an electronic product code), which may be a 5 numeric or alphanumeric string that is associated with a single entity (e.g., the blood

separation device 1) within a given system (e.g., the separation system), to be transmitted to the central control unit. For example, the identification module 14 can be a radio-frequency identification (RFID) chip or tag, which is capable of transmitting the unique identifier to the central control unit via a radio wave. The central control unit is capable of reading the unique o identifier carried by the radio wave and identifying the blood separation device 1 through the unique identifier. Alternatively, the identification module 14 may be an erasable

programmable read-only memory (EPROM) chip, which includes the unique identifier. The central control unit is capable of reading the unique identifier stored in the EPROM chip and identifying the blood separation device 1 through the unique identifier.

5 The beeper 15 can make a sound to tell a user that an abnormal event or a problem has occurred in the blood separation device 1. The start button 16 is adapted to send a start signal to the controller 3 to begin a process for separating the blood sample in the blood container 23. The stop button 17 is adapted to send a stop signal to the controller 3 to abort or terminate the process for separating the blood sample. The status displays 18, such as light- 0 emitting diodes (LEDs), can emit lights to alert a user to a status of the blood separation device 1, such as a power-on and/or fault status. The liquid-crystal display (LCD) 19, which is a flat-panel display or other electronic visual display that uses the light-modulating properties of liquid crystals, is adapted to display information about the process for separating the blood sample. The test port 20, such as an RS-232 serial port, is adapted to be used 5 during testing and for maintenance to download logs and to allow non-user diagnostics.

The power entry module 21, for example, can be an electromechanical component used in the blood separation device 1, integrating a power inlet with other components such as a switch and a fuse holder. The power entry module 21 is adapted to connect to an external power source by a power supply cord and provide alternating current (AC) power o input to the AC-to-DC power supply module 22. The AC-to-DC power supply module 22, such as an AC-to-DC voltage converter, is adapted to convert AC power from the power entry module 21 to direct current (DC) power to power all of the components 3-20. The blood separation device 1 can further include a housing, which contains the above components 3-22. A space (e.g., a socket) inside the housing is configured to accommodate the disposable cartridge 2 to be detachably locked to the blood separation device 1 by the locking mechanism 12. In the blood separation device 1, the controller 3 is adapted to control 5 and coordinate all of the components 3-22. For example, the controller 3 can perform the following operations: (1) starting a process for separating the blood sample after receiving a start command or signal from the central control unit or from the start button 16, (2) operating the locking mechanism 12 to lock the disposable cartridge 2 after receiving a command or signal from the central control unit or the start button 16 or to unlock the o disposable cartridge 2 after receiving a command or signal from the central control unit or the stop button 17, (3) monitoring a circuitry of the pump driver 5 to detect excessive current if the first syringe 24 is stuck or no current if the first syringe 24 is improperly engaged with the pump driver 5, (4) completing the process even if the wireless or wired communication drops out, and (5) aborting the process after receiving a stop command or signal from the central 5 control unit or from the stop button 17. The controller 3 may contain a battery backed up clock/timer to allow monitoring of the process for separating the blood sample for elapsed processing time even through a loss of power. Alternatively, the blood separation device 1 may contain a keep-alive circuit, which is adapted to receive periodic pulses (at least once per second) from the controller 3. If two or more pulses are missed or not received by the keep- o alive circuit from the controller 3, power to the pump driver 5 and to the cooling module 6 is turned off.

In summary, the separation system includes the blood separation device 1 (capable of communication with a central control unit) illustrated in Fig. 1 and the single-use cartridge 2 illustrated in Fig. 1 or 2 configured to be fitted in the blood separation device 1. The central 5 control unit is adapted to run software to allow a user to control one or more functions of the blood separation device 1 by wireless or wired communication. The blood separation device 1 can communicate with the central control unit through its wireless module 13 or its Ethernet module. The blood separation device 1 includes a reusable piece of equipment composed of the all of the electronic, mechanical, optical and thermal control devices (e.g., 0 the components 3-22) necessary to safely perform blood separation.

In another embodiment, a separation system is provided which includes at least two blood separation devices 1 (each as illustrated in Fig. 1) and at least two single-use cartridges 2 (each as illustrated in Fig. 1 or 2) adapted to be fitted in the respective blood separation devices 1. A central control unit is adapted to run software to allow a user to control the function of one or more of the blood separation devices 1 by wireless or wired

communication. Each of the blood separation devices 1 can communicate with the central 5 control unit through its wireless module 13 or its Ethernet module. The central control unit is capable of connecting to a peripheral device able to read a serialized unique identifier integrated into each of the cartridges 2. For example, the peripheral device can be a barcode reader, and the serialized unique identifier can be a printed barcode. Alternatively, the peripheral device can be a radio-frequency identification (RFID) reader, and the serialized o unique identifier can be a RFID code. Each of the serialized unique identifiers, for example, can be linked to an individual patient's information and read at one or more points during processing and treatment in order to prevent accidental exchange of patient samples. Each of the blood separation devices 1 includes a reusable piece of equipment composed of the all of the electronic, mechanical, optical and thermal control devices (e.g., the components 3-22) 5 necessary to safely perform blood separation.

A process for separating the blood sample using the separation system is illustrated in Fig. 5. Referring to Fig. 5, in a step SI, the blood sample is aseptically drawn from the blood, e.g., peripheral blood, of the subject into the blood container 23, containing a divalent cation chelating-based anticoagulant (e.g., EDTA or citrate), inside the disposable cartridge 2, o and the blood sample is mixed with the divalent cation chelating-based anticoagulant. In a step S2, the disposable cartridge 2 is inserted or fitted into the blood separation device 1, i.e., into a socket inside the housing of the blood separation device 1, and the blood container 23 with the blood sample inside the disposable cartridge 2 is held by the holder 11. The disposable cartridge 2 is inserted or fitted into the blood separation device 1 such that the 5 blood container 23 is in an upright position. Accordingly, each of the two openings 23 a and

23b of the blood container 23 in the disposable cartridge 2 fitted into the blood separation device 1 is at the top of the blood container 23 and at a level higher than the blood sample in the blood container 23 of the disposable cartridge 2 in a gravity coordinate.

Next, the blood separation device 1 sequentially performs the following steps S3-S5 o after receiving a start signal from the central control unit or from the start button 16 of the blood separation device 1. In a step S3, the cooling module 6 of the blood separation device 1 is driven to cool the blood sample in the blood container 23 of the disposable cartridge 2 and keep it at a specific temperature for a predetermined period of time, e.g., 3 to 72 hours, 3 to 12 hours, 3 to 18 hours, 3 to 24 hours, 3 to 36 hours, 3 to 48 hours, 3 to 60 hours, 6 to 72 hours, 6 to 12 hours, 6 to 18 hours, 6 to 24 hours, 6 to 36 hours, 6 to 48 hours, 6 to 60 hours, 12 to 72 hours, 12 to 18 hours, 12 to 24 hours, 12 to 36 hours, 12 to 48 hours, 12 to 60 hours, 5 16 to 72 hours, 16 to 18 hours, 16 to 24 hours, 16 to 36 hours, 16 to 48 hours, 16 to 60 hours, 24 to 72 hours, 24 to 36 hours, 24 to 48 hours, 24 to 60 hours, 36 to 72 hours, 36 to 48 hours, 36 to 60 hours, 48 to 72 hours, or 48 to 60 hours. The specific temperature may be between 2°C and 12°C, e.g., 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 2 to 7°C, 2 to 10°C, 4 to 8°C, 4 to 12°C, or 6 to 12°C. After having been stored at the specific temperature o for the predetermined period of time, the blood sample in the blood container 23 of the

disposable cartridge 2 fitted into the blood separation device 1 separates into two or more separate layers, which include an upper layer and a lower layer, because of gravity, e.g., gravity alone. The upper layer of the blood sample contains the suspended small cells, such as the small stem-like cells (e.g., the small somatic stem cells) and the platelets. The platelets5 in the upper layer of the blood sample may be non-viable, for example. The lower layer of the blood sample contains the deposited large cells, such as the large somatic stem cells, the red blood cells and the white blood cells. Accordingly, in the step S3, the blood separation device 1 functions by allowing the gravity-driven sedimentation of the large cells (e.g., the red and white blood cells) to occur within the blood container 23 of the disposable cartridge 0 2, and the predetermined period of time is considered as a sedimentation time.

In a step S4, the controller 3 transmits a first driving signal to the pump driver 5 after gravity separation. After receiving the first driving signal, the pump driver 5 drives the first plunger 24b to pull the first plunger 24b along the axial direction of the first barrel 24a with respect to the first barrel 24a. Accordingly, the upper layer of the blood sample in the blood 5 container 23 is pumped out of the blood container 23 through the tube 26a, the check valve

27, the tube 26b, and the first opening 24c in sequence into the first barrel 24a. In the meanwhile, the RBC detection module 4 detects whether there are red blood cells in the blood sample at a detection point 30 as the blood sample flows through the tube 26a, so as to generate a detection signal to be transmitted to the controller 3, which is transmitted to and o received by the controller 3. When the RBC detection module 4 detects light that indicates red blood cells reaching the tube 26a at the detection point 30, it generates a detection signal and transmits the detection signal to the controller 3. After receiving the detection signal transmitted from the RBC detection module 4, the controller 3 generates a second driving signal and transmits the second driving signal to the pump driver 5. After receiving the second driving signal from the controller 3, the pump driver 5 stops pulling the first plunger 24b and drawing the blood sample into the first barrel 24a. In a step S5, the controller 3

5 generates a third driving signal to command the pump driver 5 to push the first plunger 24b along the axial direction of the first barrel 24a with respect to the first barrel 24a, such that a portion of the upper layer of the blood sample collected in the first barrel 24a flows through the tube 26c into the second barrel 25a. Once the second barrel 25a is filled with the upper layer of the blood sample, the controller 3 generates a fourth driving signal to command the o pump driver 5 to stop pushing the first plunger 24b and stop driving the upper layer of the blood sample collected in the first barrel 24a to flow into the second barrel 25a. The process for separating the blood sample is then completed, and the blood separation device 1 signals the central control unit.

The blood separation device 1 continues to safely maintain the disposable cartridge 25 at the above-mentioned specific temperature (e.g., between 2°C and 12°C) until the

disposable cartridge 2 is removed by a user. After the disposable cartridge 2 is removed from the blood separation device 1, the first and second syringes 24 and 25 containing the upper layer of the blood sample can be detached from the disposable cartridge 2 for use by a person, e.g., a clinician, doctor or researcher. The upper layer of the blood sample in either the first o syringe 24 or the second syringe 25 can be used as a therapeutic cell mixture or a stem-cell containing solution for treating a disease or disorder, such as a cancer, arthritis (e.g., osteoarthritis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis), tendonitis, tendon injury or an autoimmune disease or disorder (e.g., rheumatoid arthritis, ankylosing spondylitis, or systemic lupus erythematosus), for treating joints, (muscle) tendon, (knee) 5 articular cartilage, shoulder or spine, or for applying to a bone- or joint-related treatment

(e.g., a dental implant treatment). The upper layer of the blood sample in either the first syringe 24 or the second syringe 25 may be kept for other uses, such as medical analysis.

The blood separation device 1 may be operated at the point of care by a medical technician, nurse or physician according to provided protocols. The separation system is o adapted to prepare a stem cell-containing solution (i.e., the upper layer of the blood sample) from a patient's whole blood at the point of care. The term "autologous cell" refers to a cell that is genetically an individual's own. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present disclosure to its fullest extent.

OTHER EMBODIMENTS

All of the features disclosed in this specification may be combined in any

combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.

From the above description, one skilled in the art can easily ascertain the essential characteristics of the described embodiments, and without departing from the spirit and scope thereof, can make various changes and modifications of the embodiments to adapt it to various usages and conditions. Thus, other embodiments are also within the claims.

Claims

WHAT IS CLAIMED IS:
1. A separation system, comprising:
a blood separation device containing a controller , a red-blood-cell (RBC) detection 5 module, and a pump driver; and
a cartridge configured to be reversibly attached to the blood separation device, the cartridge including:
(i) a first container configured to contain a blood sample, wherein the first container includes a first opening;
o (ii) a tubing in fluid flow communication with the first opening;
(iii) a pump in fluid flow communication with the tubing, wherein the pump is configured to move a fluid from the first container to the pump and to contain a fluid; and
(iv) a check valve mounted to the tubing, wherein the check valve is configured to allow a fluid to flow from the first container to the pump and to not allow a fluid to flow from 5 the pump to the first container.
2. The system of claim 1, wherein the RBC detection module is configured to (i) detect red blood cells in the tubing at a detection point positioned between the first opening and the pump, and (ii) generate a first signal to be transmitted to the controller when red o blood cells are detected in the tubing.
3. The system of claim 2, wherein the RBC detection module is configured to emit a light to the detection point and to detect reflection, scattering, absorption or fluorescence of the light that specifically indicates the presence of red blood cells in the fluid.5
4. The system of claim 2 or 3, wherein the controller is configured to receive the first signal from the RBC detection module, and after receiving the first signal, generate a second signal to be transmitted to the pump driver. 0
5. The system of claim 4, wherein the pump driver is configured to receive the second signal, and after receiving the second signal, drive the pump to stop moving a fluid from the first container to the pump.
6. The system of any of claims 1-5, wherein the blood separation device further includes a temperature sensor configured to detect a temperature of a fluid in the first container and to generate a third signal to be transmitted to the controller when the temperature is detected.
5
7. The system of claim 6, wherein the blood separation device further includes a cooling driver coupled to the controller, and wherein the controller is configured to, after receiving the third signal, generate and transmit a fourth signal to the cooling driver. 0
8. The system of claim 7, wherein the cooling driver is configured to receive the fourth signal, and after receiving the fourth signal, drive the cooling module to modulate the temperature of a fluid in the first container.
9. The system of any of claims 1-8, wherein the separation device further
5 includes a holder configured to press the first container against the cooling module.
10. The system of any of claims 1-9, wherein the separation device further includes a heatsink adapted to transfer heat from the cooling module to the ambient of the blood separation device.
0
11. The system of any of claims 1-10, wherein the cartridge further includes a second container in fluid flow communication with the pump, wherein the pump is adapted to move a fluid from the pump to the second container. 5 12. The system of claim 11, wherein the pump driver is configured to, after
receiving a driving signal from the controller, drive the pump to move a fluid from the pump to the second container.
13. The system of any of claims 1-12, wherein the cartridge is adapted to, when o fitted in the blood separation device, allow separation of a blood sample in the first container into an upper layer and a lower layer by gravity.
14. The system of claim 1-13, wherein the pump and the second container are both configured to be reversibly attached to the cartridge.
15. The system of any of claims 1-14, wherein the separation device is configured 5 to communicate with a central control unit via wireless communication.
16. The system of any of claims 1-15, wherein the separation device is configured to reversibly lock the cartridge in the separation device. 0
17. A method of separating a blood sample, comprising:
providing a cartridge including (i) a first container that contains a blood sample mixed with a divalent cation chelating anticoagulant, wherein the first container includes a first opening; (ii) a tubing in fluid flow communication with the first opening; (iii) a pump in fluid flow communication with the tubing, wherein the pump is reversibly attached to the cartridge 5 and is configured to move a fluid from the first container to the pump and to hold a fluid; and (iv) a check valve mounted to the tubing, wherein the check valve is configured to allow a fluid to flow from the first container to the pump and to not allow a fluid to flow from the pump to the first container, wherein the cartridge is configured to be reversibly attached to a blood separation device;
o attaching the cartridge to the blood separation device such that the first container is in an upright position and the first opening is at the top of the container;
cooling the blood sample in the first container to 2°C and 12°C;
maintaining the blood sample at 2°C and 12°C for 6 to 72 hours, whereby the blood sample separates into an upper layer and a lower layer by gravity; and
5 pumping a portion of the upper layer out of the first container to the pump through the first opening and the tubing until red blood cells are detected in the tubing at a detection point positioned between the first opening and the pump, wherein the pump holds the portion of the upper layer. 0
18. The method of claim 19, wherein the cartridge further includes a second
container in fluid flow communication with the pump, the method further comprising a step of pumping a part of the portion of the upper layer in the pump to the second container, wherein the second container holds the part of the portion of the upper layer.
19. The method of claim 18, further comprising removing the cartridge from the
5 blood separation device and detaching the pump and the second container from the cartridge.
20. The method of claim 17, wherein the blood separation device contains a red- blood-cell (RBC) detection module and a pump driver, wherein the RBC detection module is configured to detect red blood cells in the tubing at the detection point, and the pump driver is o configured to drive the pump to move a fluid from the first container to the pump and to move a fluid from the pump to the second container.
21. A blood separation device comprising:
a controller;
5 a cooling module configured to cool a blood sample;
a red-blood-cell (RBC) detection module configured to detect red blood cells of a blood sample at a detection point and to generate a first signal if red blood cells are detected; and
a pump driver configured to drive a blood sample to flow through the detection point.0
22. The blood separation device of claim 21, wherein the controller is configured to receive the first signal from the RBC detection module, and after receiving the first signal, generate a second signal to be transmitted to the pump driver. 5 23. The blood separation device of claim 21, further comprising a holder
configured to hold and press a container against the cooling module.
24. The blood separation device of claim 21, wherein the RBC detection module is configured to emit a light to the detection point and to detect reflection, scattering, o absorption or fluorescence of the light that specifically indicates the presence of red blood cells in the fluid.
25. The blood separation device of claim 21, further comprising a housing containing the RBC detection module, the pump driver, and the cooling module, wherein a space inside the housing is configured to accommodate a cartridge to be detachably locked to the blood separation device.
26. A cartridge configured to be fitted in the blood separation device of claim 21, comprising:
a first container configured to contain a blood sample, wherein the cartridge is configured to be fitted in the blood separation device such that the first container held in an upright position in the blood separation device and an opening is positioned at the top of the first container;
a tubing in fluid flow communication with the opening;
a pump in fluid flow communication with the tubing, wherein the pump is configured to contain a fluid; and
a check valve mounted to the tubing, wherein the check valve is configured to allow a fluid to flow from the first container to the pump and to not allow a fluid to flow from the pump to the first container.
27. The cartridge of claim 26, further comprising a second container in fluid flow communication with the pump, wherein the second container container is configured to contain a fluid flowing from the pump to the second container.
28. The cartridge of claim 26, further comprising a filter mounted to the tubing, wherein the filter is configured to filter leukocytes from a fluid flowing through the tubing.
PCT/US2017/028793 2016-04-22 2017-04-21 Blood separation system WO2017184954A1 (en)

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JP2018554690A JP2019514477A (en) 2016-04-22 2017-04-21 Blood separation system
EP17786696.9A EP3445417A4 (en) 2016-04-22 2017-04-21 Blood separation system
CN201780024477.5A CN109069709A (en) 2016-04-22 2017-04-21 Blood separation system

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JP2019514477A (en) 2019-06-06
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CN109069709A (en) 2018-12-21
EP3445417A1 (en) 2019-02-27

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