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WO2017041102A1 - Procédés et dispositifs de séparation acoustique du sang - Google Patents

Procédés et dispositifs de séparation acoustique du sang Download PDF

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Publication number
WO2017041102A1
WO2017041102A1 PCT/US2016/050415 US2016050415W WO2017041102A1 WO 2017041102 A1 WO2017041102 A1 WO 2017041102A1 US 2016050415 W US2016050415 W US 2016050415W WO 2017041102 A1 WO2017041102 A1 WO 2017041102A1
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WIPO (PCT)
Prior art keywords
blood
flow chamber
standing wave
acoustic
acoustic standing
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2016/050415
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English (en)
Inventor
Rudolf Gilmanshin
Bart Lipkens
Brian DUTRA
Daniel Kennedy
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Flodesign Sonics Inc
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Flodesign Sonics Inc
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Filing date
Publication date
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Publication of WO2017041102A1 publication Critical patent/WO2017041102A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3678—Separation of cells using wave pressure; Manipulation of individual corpuscles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3692—Washing or rinsing blood or blood constituents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B06—GENERATING OR TRANSMITTING MECHANICAL VIBRATIONS IN GENERAL
    • B06B—METHODS OR APPARATUS FOR GENERATING OR TRANSMITTING MECHANICAL VIBRATIONS OF INFRASONIC, SONIC, OR ULTRASONIC FREQUENCY, e.g. FOR PERFORMING MECHANICAL WORK IN GENERAL
    • B06B1/00—Methods or apparatus for generating mechanical vibrations of infrasonic, sonic, or ultrasonic frequency
    • B06B1/02—Methods or apparatus for generating mechanical vibrations of infrasonic, sonic, or ultrasonic frequency making use of electrical energy
    • B06B1/06—Methods or apparatus for generating mechanical vibrations of infrasonic, sonic, or ultrasonic frequency making use of electrical energy operating with piezoelectric effect or with electrostriction
    • B06B1/0644—Methods or apparatus for generating mechanical vibrations of infrasonic, sonic, or ultrasonic frequency making use of electrical energy operating with piezoelectric effect or with electrostriction using a single piezoelectric element
    • B06B1/0662—Methods or apparatus for generating mechanical vibrations of infrasonic, sonic, or ultrasonic frequency making use of electrical energy operating with piezoelectric effect or with electrostriction using a single piezoelectric element with an electrode on the sensitive surface
    • B06B1/0674—Methods or apparatus for generating mechanical vibrations of infrasonic, sonic, or ultrasonic frequency making use of electrical energy operating with piezoelectric effect or with electrostriction using a single piezoelectric element with an electrode on the sensitive surface and a low impedance backing, e.g. air
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/04—Liquids
    • A61M2202/0413—Blood
    • A61M2202/0427—Platelets; Thrombocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/04—Liquids
    • A61M2202/0413—Blood
    • A61M2202/0429—Red blood cells; Erythrocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/04—Liquids
    • A61M2202/0413—Blood
    • A61M2202/0456—Lipoprotein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/08—Lipoids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/02—General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0244—Micromachined materials, e.g. made from silicon wafers, microelectromechanical systems [MEMS] or comprising nanotechnology

Definitions

  • Cardiopulmonary bypass surgery is a common procedure whereby the function of the heart and lungs are taken over by a pump system commonly called a heart-lung machine. Cardiopulmonary bypass surgery is commonly used in coronary bypass heart surgery due to the difficulty of operating on a beating heart. This surgical procedure is also used for the repair of cardiac valves, organ transplants, repair of large aneurysms, and other life-saving procedures.
  • One of the issues associated with cardiopulmonary bypass surgery is injury to the patient due to strokes caused by micro- emboli. These microemboli are many times caused by lipids that result from the incision into the thoracic cavity through the sternum. Sternal bone marrow contains a large amount of lipids.
  • the lipids wash into the pool of pericardial blood from the sternum and the incision through several tissues, particularly the large amount of fat that is found in the stomach of older patients. This blood is often scavenged with a suction line and returned to the patient through the heart-lung machine. Perioperative use of the patient's own blood is a common practice in cardiac, trauma, and orthopedic surgery.
  • filters clog and suffer from throughput constraints are replaced in practice, potentially multiple times, and may break up larger droplets into smaller droplets. Centrifugation is time-consuming, expensive, and is implemented using trained personnel. Also, the high speeds used for centrifugation may damage the blood cells, and removes beneficial blood components such as platelets and clotting factors.
  • MEMS devices have been used, but rely on very small passages that essentially "line up" red blood cells and lipid particles for separation. This process results in very low throughput, and cannot handle large amounts in bulk. Additionally, these devices and methods also suffer from limitations of potential fragmentation and deformation of red blood cells (RBCs), and the potential to activate clotting or inflammatory cascades. Moreover, the time to process the blood in these devices, which work in a "batch" mode, prevents the immediate re-transfusion of blood to the patient.
  • RBCs red blood cells
  • red blood cells erythrocytes
  • white blood cells leukocytes
  • platelets are used in various therapeutic operations in their separated form.
  • the present disclosure relates, in various embodiments, to acoustophoretic devices with improved fluid dynamics that can be used to improve the separation of blood components and/or lipids from blood. More particularly, the devices include a flow chamber containing an ultrasonic transducer and reflector that set up a multidimensional acoustic standing wave.
  • acoustophoresis devices for separating components (e.g., red blood cells (RBCs), white blood cells (leukocytes), platelets, lipids) from blood (e.g., during surgery).
  • the device comprises a flow chamber through which is flowed blood containing blood components, an ultrasonic transducer positioned on a wall of the flow chamber and a reflector located on a wall of the flow chamber opposite the ultrasonic transducer, an inlet on a first side of the flow chamber; a filtrate outlet; and a concentrate outlet below the acoustic standing wave.
  • the ultrasonic transducer includes a piezoelectric material driven by a voltage signal to create a multi-dimensional acoustic standing wave in the acoustic chamber.
  • the filtrate outlet is located above the acoustic standing wave.
  • the flow chamber further comprises a lipid collection trap above the acoustic standing wave, and the filtrate outlet is located on a second side of the flow chamber opposite the first side thereof.
  • the flow chamber can further comprise a shallow wall tapered from the filtrate outlet to the concentrate outlet.
  • the device can further comprise a container (e.g., bag) detachably connected to the concentrate outlet.
  • the container can be configured to automatically seal upon detachment from the concentrate outlet without comprising the sterility of any material held within the container.
  • the container may be a disposable bag capable of withstanding temperatures from about -80 °C to about 40 °C.
  • the flow chamber can have an interior volume of at least 50 ml_.
  • a portable, autonomous system comprising an acoustophoretic device according to the present disclosure that is battery-powered.
  • the method comprises flowing the blood through a flow chamber and driving the ultrasonic transducer by a voltage signal to generate a multi-dimensional acoustic standing wave in the blood, wherein each acoustic standing wave exerts an acoustic radiation force, such that blood components, such as, for example, the red blood cells, are trapped in the acoustic standing wave against fluid drag force.
  • the blood can be undiluted whole blood and can be flowed through the flow chamber at a flow rate of at least two liters per hour.
  • the trapped red blood cells may coalesce or agglomerate such that they are separated through enhanced gravitational settling.
  • the method may further comprise a step of washing the red blood cells with at least one solvent (e.g., watery solvents, high concentration glycerol solvents) to remove undesired admixtures therefrom.
  • the at least one solvent can be introduced into the flow chamber while the red blood cells are trapped within the acoustic standing wave.
  • the blood Prior to the washing step, the blood may be diluted, such as with saline (e.g., phosphate buffered saline).
  • saline e.g., phosphate buffered saline
  • the blood may be undiluted whole blood and may be combined with the at least one solvent into a single flow that is flowed through the flow chamber at a flow rate of at least 4.5 mL/min.
  • a cryoprotectant may be added or removed from the blood.
  • the blood may further include platelets.
  • the ultrasonic transducer can be driven at varying frequencies to selectively isolate the red blood cells and platelets from the blood without causing hemolysis of the red blood cells or activation of the platelets.
  • Blood fluid includes surgical blood, or blood that may be combined with components typically not found in blood, such as lipids, clots, bone fragments and other material that may result from surgery, injury or trauma.
  • the methods may include flowing the blood fluid through a flow chamber of an acoustophoretic device, generating a multi-dimensional acoustic standing wave in the flow chamber to impose an acoustic radiation force on the blood fluid, such that the lipids in the blood fluid are retained and grouped to form larger groups of lipids in the acoustic standing wave against fluid drag force.
  • the multi-dimensional standing wave results in an acoustic radiation force having an axial force component and a lateral force component that are the same order of magnitude.
  • the acoustic standing wave may be a multi-dimensional acoustic standing wave (e.g., a three-dimensional acoustic standing wave). Examples of such multi-dimensional acoustic standing waves can be found in commonly owned U.S. Patent No. 9,228,183, the entire contents of which are hereby fully incorporated by reference.
  • the acoustic standing wave can be a planar acoustic standing wave.
  • the acoustic standing wave may be a combination of a planar acoustic standing wave and a multi-dimensional acoustic standing wave, such as where the planar acoustic standing wave and multidimensional acoustic standing wave are super- positioned on each other.
  • Some disclosed embodiments provide systems and/or methods for separating blood components and lipids from blood utilizing techniques that do not harm the blood component cells (e.g., erythrocytes, leukocytes, platelets) and that can be performed continuously, for example so blood can be recirculated during surgery. Some embodiments act to reduce the amount of lipids that are present in blood during surgery, so as to reduce microemboli and minor or major strokes in the patient.
  • the blood component cells e.g., erythrocytes, leukocytes, platelets
  • FIG. 1A is an exterior side view of a first exemplary embodiment of an acoustophoretic device according to the present disclosure.
  • FIG. 1 B is an exterior view of the first embodiment from the front.
  • FIG. 1 C is an exterior view of the first embodiment from the top.
  • FIG. 2 is an interior sidecross-sectional view that illustrates additional features of the acoustophoretic device of FIG. 1 A.
  • FIGS. 3A-3D are diagrams illustrating acoustophoretic separation methods according to the present disclosure.
  • FIG. 3A is a top view of a flow chamber and shows red blood cells (darker circles) and lipid particles (lighter circles) entering the system from the left-hand side and flowing horizontally therethrough.
  • FIG. 3B is a top view of the flow chamber and shows the red blood cells and lipids becoming axially aligned in the acoustic standing wave.
  • FIG. 3C is another top view of the flow chamber and shows the red blood cells and lipids agglomerating into clumps in well-defined striated columns due to the lateral force component of the acoustic standing wave.
  • FIG. 3A is a top view of a flow chamber and shows red blood cells (darker circles) and lipid particles (lighter circles) entering the system from the left-hand side and flowing horizontally therethrough.
  • FIG. 3B is a top view of the flow chamber and shows the red blood cells and lipid
  • 3D is a cross-sectional side view of the flow chamber and shows that some of the red blood cells have agglomerated to a sufficient size and sunk to the bottom of the flow chamber, while the lipids have agglomerated to a sufficient size and risen to the top of the flow chamber.
  • FIG. 4 is a diagram that illustrates a system for testing / operating an acoustophoretic device according to the present disclosure.
  • the components includes a laptop, a transducer control module, a pump module, an inflow reservoir, a buffer reservoir, an acoustic filtration system (e.g. , an acoustophoretic device according to the present disclosure), and a filtrate reservoir.
  • FIG. 5 is an interior side cross-sectional view that illustrates the fluid flow path through the acoustophoretic device of FIG. 1.
  • Fluid e.g. , blood
  • the filtrate i.e., clarified fluid
  • the concentrated cells exit the device at a flow rate V c .
  • FIG. 6 shows the performance of the acoustophoretic device of FIG. 5.
  • FIG. 6A is a chart that presents the red blood cell collection percentage of the device at different combinations of the feed flow rate (V in ) and of the ratio of the flow rates of the filtrate outlet (V f ) and the concentrate outlet (V c ).
  • FIG. 6B is a chart that presents the red blood cell concentration factor of the device at different combinations of the feed flow rate (V in ) and of the ration of the flow rates of the filtrate outlet (V f ) and the concentrate outlet (V c ).
  • FIGS. 7A-7E are images that illustrate a lipid image analysis at 40x magnification.
  • FIG. 7A shows lipid particles in saline immediately after spike.
  • FIG. 7B shows the lipid particles in saline after filtration through a physical filter.
  • FIG. 7C shows the lipid particles in saline after undergoing acoustic filtration according to the present disclosure.
  • FIG. 7D shows the lipid particles in saline after agglomerating and rising to a lipid collection trap at the top of a flow chamber.
  • FIG. 7E shows a top view of the lipid collection trap after filtration of the lipid particles according to the present disclosure.
  • FIG. 8 is a graph illustrating the acoustic effect on the blood components, namely platelet aggregation in blood that was examined after separation and reconstitution according to the present disclosure.
  • the y-axis is percent aggregation, and runs from -10 at the top to 100 at the bottom in intervals of 10.
  • the x-axis is time in seconds, and runs from 0 at the left to 660 at the right in intervals of 60.
  • FIG. 9A is a graph illustrating the acoustic effect on the blood components, namely fibrin formation in (i) control blood and (ii) blood that was processed through an acoustic standing wave system.
  • the y-axis is in nanograms per milliliter (ng/mL), and runs from 0 to 2500 in intervals of 500.
  • FIG. 9B is a graph illustrating the amount of activated complements on the blood of FIG. 9A.
  • the y-axis is in picograms per ml_ (pg/mL), and runs from -50 to 250 in intervals of 50.
  • IL-6 is the left-hand bar and TNF-a is the right-hand bar for both "control" and "AWS processed”.
  • FIG. 10 is a graph measuring hemolysis of red blood cells in (i) control blood and (ii) blood that was processed through an acoustic standing wave system.
  • the y-axis runs from 0 to 50 in intervals of 10.
  • haptoglobin the units are ng/mL.
  • LDH the units are Units per liter (U/L).
  • Haptoglobin is the left-hand bar and LDH is the right-hand bar for both "control" and "AWS processed”.
  • FIG. 11A is a graph illustrating the effect on the systolic blood pressure of blood filtered by acoustophoresis in accordance with the present disclosure that was auto-transfused into two porcines undergoing surgery.
  • the y-axis is in mmHg, and runs from 0 to 125 in intervals of 25.
  • FIG. 11 B is a graph illustrating the effect on mean arterial pressure of the processed blood.
  • the y-axis is in mmHg, and runs from 0 to 75 in intervals of 25.
  • FIG. 12 is an image that illustrates a first exemplary embodiment of a portable, autonomous acoustophoretic system according to the present disclosure.
  • the system includes a battery-powered acoustophoretic device according to the present disclosure. Also visible is tubing and at least two separate bags (the first to provide a source of blood to the device, the second to receive separated blood components).
  • the various components are housed in a portable container, such as the suitcase shown here.
  • FIG. 13 is a diagram illustrating an acoustophoretic separation method according to the present disclosure for a particle or blood component (e.g., lipids) less dense than a host fluid (e.g., blood).
  • FIG. 14 is a diagram illustrating an acoustophoretic separation method according to the present disclosure for a particle or blood component (e.g., red blood cells) denser than a host fluid (e.g., blood).
  • a particle or blood component e.g., red blood cells
  • FIG. 15 is a cross-sectional diagram of a conventional ultrasonic transducer.
  • FIG. 16 is a cross-sectional diagram of an ultrasonic transducer of the present disclosure. An air gap is present within the transducer, and no backing layer or wear plate is present.
  • FIG. 17 is a cross-sectional diagram of an ultrasonic transducer of the present disclosure. An air gap is present within the transducer, and a backing layer and wear plate are present.
  • FIG. 18 is a graph showing the relationship of the acoustic radiation force, gravity / buoyancy force, and Stokes' drag force to particle size.
  • the horizontal axis is in microns (pm) and the vertical axis is in Newtons (N).
  • FIG. 19 is a graph of electrical impedance amplitude versus frequency for a square transducer driven at different frequencies.
  • FIG. 20A is an illustration of the trapping line configurations for seven peak amplitudes of an ultrasonic transducer of the present disclosure.
  • FIG. 20B is a perspective view illustrating a separator of the present disclosure. The fluid flow direction and the trapping lines are shown.
  • FIG. 20C is a view from the fluid inlet along the fluid flow direction (arrow 814) of FIG. 20B, showing the trapping nodes of the standing wave where particles would be captured.
  • FIG. 20D is a view taken through the transducers face at the trapping line configurations, along arrow 816 as shown in FIG. 20B
  • the modifier "about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context. When used in the context of a range, the modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the range of “from about 2 to about 10” also discloses the range “from 2 to 10.”
  • the term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 1 1 %, and “about 1 " may mean from 0.9-1 .1.
  • the terms “upper” and “lower” are relative to each other in location, i.e. an upper component is located at a higher elevation than a lower component in a given orientation, but these terms can change if the device is flipped.
  • the terms “inlet” and “outlet” are relative to a fluid flowing through them with respect to a given structure, e.g. a fluid flows through the inlet into the structure and flows through the outlet out of the structure.
  • upstream and “downstream” are relative to the direction in which a fluid flows through various components, i.e. the flow fluids through an upstream component prior to flowing through the downstream component. It should be noted that in a loop, a first component can be described as being both upstream of and downstream of a second component.
  • top and bottom are used to refer to surfaces where the top is always higher than the bottom/base relative to an absolute reference, i.e. the surface of the earth.
  • upwards and “downwards” are also relative to an absolute reference; upwards is always against the gravity of the earth.
  • the present application refers to "the same order of magnitude.” Two numbers are of the same order of magnitude if the quotient of the larger number divided by the smaller number is a value of at least 1 and less than 10.
  • blood refers to the combination of blood cells suspended in plasma.
  • plasma refers to the liquid component of blood that contains dissolved proteins, glucose, clotting factors, mineral ions, hormones and carbon dioxide.
  • blood cells refers to both red blood cells and white blood cells.
  • the term "crystal” refers to a single crystal or polycrystalline material that is used as a piezoelectric material.
  • the present disclosure relates to systems and methods for separating RBCs and lipid contaminants from blood using multi-dimensional acoustic standing waves (ASWs). These systems and methods also provide the potential to perform washing of blood cells, which makes them particularly desirable for the healthcare market.
  • the systems and methods according to the present disclosure combine ASW-based inherent advantages, such as efficient separation, low power consumption, controllability, and gentle cell handling, with the sufficiently high throughput demanded by many clinical and healthcare applications.
  • the filtration efficiency for lipid separation using these ASW-based systems can be better than that of conventional methods, such as filter screens and centrifugation, because agglomeration and coalescence of smaller particles in the present ASW-based systems and methods permit capture and removal of lipid particles too small for filters and centrifuges.
  • CT component therapy
  • RBCs red bloods cells
  • platelets or plasma.
  • RBCs accumulate structural and biochemical damage due to ex vivo storage at 4 °C. Adverse effects from this damage can be managed by cell washing procedures that remove ineffective RBCs and metabolic degradation products and markedly improve the quality of the product to be transfused.
  • a similar treatment can also potentially restore usability of an RBC concentrate that is weeks past its shelf life.
  • cryopreservation While the typical storage period of packed RBCs is limited per regulatory guidelines to only several weeks in common practice, when the products are preserved in liquid state at 4 °C, the storage period can be extended up to at least 10 years (and possibly for several decades) by cryopreservation. [0057] In emergency situations, such as natural disasters, wars, and acts of terror, transfusions of blood products may be urgently life-saving, but due to logistical and transportation issues, routinely stocked clinical blood banks may be incapable of meeting the increased demands quickly and effectively. In such situations, the use of cryopreserved stocks, as well as potentially the use of expired blood restored by washing procedures, may help to stabilize patients during the critical first hours of care. High numbers of patients with massive trauma is another hallmark of such emergencies.
  • Blood processing systems typically used in clinical practice are large, heavy, and power-hungry devices that are operated by trained personnel. Therefore, these systems are largely restrained to clinical use, and their application in field conditions is hardly practical. Available systems are highly specialized.
  • the systems used to process blood collected from surgical fields prior to reinfusion (such as Cell Saver 5+, Haemonetics, MA) differ from those used in blood banking for washing and cryoprotectant management (such as ACP 215, Haemonetics, or CaBE 2991 , Terumo, Shibuya, Japan).
  • the systems and devices of the present disclosure utilize multi-dimensional acoustic standing waves (ASWs).
  • ASWs acoustic standing waves
  • An important feature of ASW-based systems is their small size and low power consumption, which aids in portability. They are also amenable to automation and to easy maintenance, primarily because they do not include rotors driven at high speed.
  • the multidimensional (e.g., three-dimensional) ASW technology of the present disclosure permits a portable ASW system to be used for blood treatment.
  • the systems and devices of the present disclosure do not have the same limitations as prior large, heavy, and power-hungry devices. Portability of the systems and devices is enhanced by the absence of a centrifuge. Universality is another important feature that favors the systems and device of the present disclosure for emergencies.
  • the systems and devices of the present disclosure can be used to de- glycerolize RBC concentrates from deep-frozen stocks and make them available in urgent transfusions to stabilize patients. Additionally, the systems and devices can be used for purification and re-transfusion of blood loss caused by trauma.
  • One more important feature is that an ASW-based process is essentially continuous and is not limited by batch size, in contrast to present systems.
  • the systems and devices of the present disclosure can be used for blood treatment when the total volume of blood is not known a priori, which is important in trauma surgery.
  • the combination of multiple uses in a single device and high levels of automation will save valuable time for healthcare personnel, especially in emergency situations.
  • the selectivity of the acoustic standing wave(s) used herein can be modified by changing the operation frequency. The higher the frequency, the smaller the wavelength and, hence, smaller particles can be trapped. This effect may be employed for fractionation of cells by size, such as separation of platelets from RBCs and WBCs.
  • blood can be recirculated through the system for multiple process cycles. This can enhance performance of the operations that are insufficiently selective with a single cycle.
  • the ability to use multiple cycles to perform an operation may reduce the system size and the dead volume.
  • acoustics control is independent from flow control; therefore, separation by ASW technology can be augmented by combining it with fluidics manipulation.
  • the flexibility and power of such an approach have been widely demonstrated in the MEMS domain.
  • washing of RBCs in an ASW system will be more efficient due to the lack of cell compression, which is inherent in centrifugal applications.
  • Isolation of platelets and leukapheresis is also contemplated.
  • the ability to isolate and fractionate the "buffy coat" is a first step in selecting T-cells from a cancer patient blood or stem cells from umbilical cord blood. Both immune and stem cells are at the core of the rapidly growing cell therapy manufacturing.
  • the acoustophoretic systems, devices, and methods of the present disclosure advantageously provide the ability to capture, separate, and cause particles to separate out of an active fluid flow. As such, these systems, devices, and methods can replace traditional physical filtration, sedimentation, or centrifugation techniques.
  • Acoustophoresis is a low-power, no- pressure-drop, no-clog, solid-state approach for the separation of particles, secondary fluids, and / or components (e.g., red blood cells (RBCs), white blood cells (leukocytes), platelets, lipids) from a primary or host fluid (e.g., blood) using high-intensity acoustic standing waves, and without the use of membranes or physical size exclusion filters. It has been known that high intensity standing waves of sound can exert forces on particles in a fluid when there is a differential in both density and/or compressibility, otherwise known as the acoustic contrast factor.
  • the pressure profile in a standing wave contains areas of local minimum pressure amplitudes at its nodes and local maxima at its anti-nodes. Depending on the density and compressibility of the particles, they will be trapped at the nodes or anti-nodes of the standing wave. Generally, the higher the frequency of the standing wave, the smaller the particles that can be trapped due the pressure of the standing wave.
  • Acoustophoresis can be used to separate similarly sized blood cells and lipids from each other, so that either the blood cells, the lipids, or both can be collected.
  • Acoustophoresis can be used in a continuous flow process, in which the blood flows through a flow chamber, allowing a continuous loop process without any flow interruption.
  • the devices of the present disclosure can be autonomous and continuously operated, which can be particularly advantageous for certain applications, and allows for use of the devices without the need for any specially trained personnel.
  • the blood cells and lipids are separated from the plasma, and can thus be removed from the blood / plasma. This can be useful for example during surgery, when lipids are introduced into the bloodstream of a surgery patient.
  • the lipids can be removed from the bloodstream during the external circulation loop of the blood, reducing the likelihood of lipid micro-emboli due to the surgery.
  • the removal of lipids can reduce post-surgery complications.
  • FIGS. 1A-1C and FIG. 2 a first exemplary embodiment of an acoustophoretic device 100 for separating blood components (e.g., lipids, blood cells) from blood is depicted.
  • FIG. 1A is an external side view
  • FIG. 1 B is an external front view
  • FIG. 1C is an external top view
  • FIG. 2 is an interior view.
  • the device 100 includes a flow chamber 110, which can be best seen in FIG. 2.
  • the flow chamber 110 is the region of the device 100 through which blood containing blood components flows.
  • the device 100 includes an inlet 140 on a first side 102 of the flow chamber 110.
  • the flow chamber 110 further includes at least two outlets.
  • a filtrate outlet 150 is present.
  • the filtrate outlet 150 is located on a second side 104 of the flow chamber 110.
  • the second side 104 of the flow chamber 110 is located opposite the first side 102 thereof, such that, in this embodiment, the inlet 140 is located on an opposite side of the flow chamber 110 from the filtrate outlet 150.
  • a concentrate outlet 160 is also present in the flow chamber 110.
  • the concentrate outlet 160 is located at a bottom end 108 of the flow chamber 110.
  • the flow chamber 110 also includes a lipid collection trap 170 at a top end 106 thereof.
  • the top end 106 of the flow chamber 110 is located opposite the bottom end 108 thereof, such that, in this embodiment, the lipid collection trap 170 is located on an opposite end of the flow chamber 110 from the concentrate outlet 160.
  • the flow chamber 110 can have an interior volume of at least 50 ml_, such that the device 100 remains lightweight and portable.
  • the flow chamber includes an ultrasonic transducer 120 positioned on a wall thereof.
  • a reflector 130 is positioned so as to set up a multidimensional acoustic standing wave in the flow chamber, as described in detail herein.
  • the transducer 120 has a width 101 and a height 103.
  • the ultrasonic transducer-reflector pair generates the multi-dimensional acoustic standing wave in the flow chamber therebetween.
  • the acoustic standing wave is generated in the flow chamber between the ultrasonic transducer and the reflector and generally does not extend beyond those respective surfaces.
  • the lipid collection trap 170 when the lipid collection trap 170 is provided, it is located within the flow chamber 110 at the top end 106 thereof above the acoustic standing wave.
  • the filtrate outlet 150 is located on a second side 104 of the flow chamber 110 outside of the acoustic standing wave.
  • the concentrate outlet 160 is located within the flow chamber 110 at the bottom end 108 thereof below the acoustic standing wave.
  • the flow chamber 110 includes an angled wall 112 that tapers from the filtrate outlet 150 to the concentrate outlet 160.
  • the shallow wall 112 tapers from the second side 104 of the flow chamber 110 towards the bottom end 108 thereof, or put another way is opposite the inlet. In this way, at higher flow rates through the device 100, the shallow wall 112 can aid in deflecting the filtrate (i.e., clarified blood) upward towards the filtrate outlet 150 and agglomerated particles denser than the blood (e.g., blood cells) downward towards the concentrate outlet 160.
  • the shallow wall 112 further prevents any undesirable build-up or clogging of the flow chamber and minimizes the dead volume because the device contains shorter connection lines than a comparable centrifuge system, whose size is restricted by the rotor geometry.
  • the devices and systems of the present disclosure therefore have a much higher potential to eliminate fat and lipid contamination, decreasing the embolism risks of peri-operatively collected autologous blood from the surgical field for hemotherapy.
  • the filtrate outlet 150 could be located at the top end 106 of the flow chamber 110 (e.g., in the location of the lipid collection trap 170 currently depicted in FIG. 1A and FIG. 2). That is, the filtrate outlet 150 can be located in the flow chamber 110 at the top end 106 thereof above the acoustic standing wave. Put another way, no lipid collection trap is present in such embodiments.
  • the device 100 can also include a container 180 (e.g., a bag) that is detachably connected to the concentrate outlet 160.
  • the container 180 is configured to automatically seal upon detachment from the concentrate outlet 160 without comprising the sterility of any material held within the container 160.
  • Such self-sealing containers are known in the art.
  • the container 160 is usable for transfusions at body temperature and for low- temperature storage as low as -80 °C.
  • blood enters through inlet 140. Clarified blood exits through filtrate outlet 150, and concentrate exits through the concentrate outlet 160. If desired, lipids can also be removed through lipid collection trap 170. These flows are indicated with arrows.
  • the flow chamber operates as shown in FIGS. 3A-3D.
  • the transducer 120 and reflector 130 generate an acoustic standing wave that establishes pressure nodes (solid lines) and anti-nodes (dashed lines) in the acoustic standing wave between the transducer and reflector pair.
  • the axial force component of the acoustic radiation force generated by the acoustic standing wave aligns the red blood cells and lipids in the nodal/antinodal lines based on acoustic contrast factor.
  • FIG. 3C shows how the lateral force component of the acoustic radiation force generated by the acoustic standing wave causes agglomeration / coalescence of the red blood cells and lipids into clumps within the planes to create striated columns of aggregated materials.
  • FIG. 3D is a cross-sectional side view of a nodal plane and shows that as the agglomerated clumps increase in size, they either rise or sink out of the acoustic standing wave due to enhanced buoyancy or gravitational settling, respectively.
  • the red blood cells which are more dense than the plasma, agglomerate and then fall into the concentrate outlet 160 at the bottom of the flow chamber due to enhanced gravitational settling, while the lipids, which are less dense than plasma, agglomerate and rise to the lipid collection trap 170 at the top of the flow chamber due to enhanced buoyancy.
  • materials denser than plasma e.g., blood cells
  • materials denser than plasma e.g., blood cells
  • the acoustic standing wave will agglomerate or coalesce within the acoustic standing wave before growing to a sufficient size that they fall out of the acoustic standing wave due to enhanced gravitational settling and fall to the concentrate outlet 160 below the acoustic standing wave.
  • materials less dense than plasma e.g., lipids
  • the filtrate flows from the inlet 140 to the filtrate outlet 150 after being clarified of components by the acoustic standing wave.
  • the acoustophoretic device is designed to create a high intensity multidimensional (e.g., three-dimensional) acoustic standing wave that results in an acoustic radiation force that is larger than the combined effects of fluid drag and buoyancy, and is therefore able to trap, i.e., hold stationary, the suspended phase (e.g., particles or a secondary fluid).
  • the suspended phase e.g., particles or a secondary fluid.
  • the present systems and devices have the ability to create ultrasonic standing wave fields that can trap particles in flow fields with linear velocity of about 10 mL/min to about 60 Ml/min, and even higher. Excellent particle separation efficiencies have been demonstrated for particle sizes as small as one micron. As can be seen in Table 1 below, such particle sizes are much smaller than blood and lipid cells.
  • the scattering of the acoustic field off the particles results in a three-dimensional acoustic radiation force, which acts as a three-dimensional trapping field.
  • the acoustic radiation force is proportional to the particle volume (e.g., the cube of the radius) when the particle is small relative to the wavelength. It is proportional to frequency and the acoustic contrast factor. It also scales with acoustic energy (e.g. the square of the acoustic pressure amplitude).
  • the sinusoidal spatial variation of the force is what drives the particles to the stable positions within the standing waves.
  • the particle When the acoustic radiation force exerted on the particles is stronger than the combined effect of fluid drag force and buoyancy/gravitational force, the particle is trapped within the acoustic standing wave field.
  • the action of the acoustic forces (i.e., lateral and axial acoustic forces) on the trapped particles results in formation of tightly packed clusters through concentration, agglomeration and/or coalescence of particles that settle through enhanced gravity (particles heavier than the host fluid) or buoyancy (particles lighter than the host fluid).
  • secondary inter-particle forces such as Bjerkness forces, aid in particle agglomeration.
  • the axial acoustic radiation force drives the cells towards the standing wave pressure nodes.
  • the axial component of the acoustic radiation force drives the cells, with a positive contrast factor, to the pressure nodal planes, whereas cells or other particles with a negative contrast factor are driven to the pressure anti-nodal planes.
  • the radial or lateral component of the acoustic radiation force is the force that traps the cells.
  • the radial or lateral component of the ARF is larger than the combined effect of fluid drag force and gravitational force.
  • the buoyancy force F B is expressed as:
  • this equation can be used to estimate the magnitude of the lateral acoustic radiation force.
  • ⁇ indicates time averaging over the period of the wave.
  • Gork'ov's model is for a single particle in a standing wave and is limited to particle sizes that are small with respect to the wavelength of the sound fields in the fluid and the particle. It also does not take into account the effect of viscosity of the fluid and the particle on the radiation force. As a result, this model cannot be used for the macro-scale ultrasonic separators discussed herein since particle clusters can grow quite large. A more complex and complete model for acoustic radiation forces that is not limited by particle size was therefore used. The models that were implemented are based on the theoretical work of Yurii llinskii and Evgenia Zabolotskaya as described in AIP Conference Proceedings, Vol. 1474-1 , pp. 255-258 (2012). These models also include the effect of fluid and particle viscosity, and therefore are a more accurate calculation of the acoustic radiation force.
  • the lateral force of the total acoustic radiation force (ARF) generated by the ultrasonic transducers of the present disclosure is significant and is sufficient to overcome the fluid drag force. Additionally, as explained above, this action of the acoustic forces (i.e., lateral and axial acoustic forces) on the trapped particles results in formation of tightly packed clusters through concentration, agglomeration and/or coalescence of particles that settle through enhanced gravity (particles heavier than the host fluid) or buoyancy (particles lighter than the host fluid). Relatively large solids of one material can thus be separated from smaller particles of a different material, the same material, and/or the host fluid through enhanced gravitational separation.
  • AMF total acoustic radiation force
  • the multi-dimensional standing wave generates acoustic radiation forces in both the axial direction (i.e., in the direction of the standing wave, between the transducer and the reflector, perpendicular to the flow direction) and the lateral direction (i.e., in the flow direction).
  • the axial direction i.e., in the direction of the standing wave, between the transducer and the reflector, perpendicular to the flow direction
  • the lateral direction i.e., in the flow direction.
  • the lateral acoustic radiation force then acts to move the concentrated particles towards the center of each planar node, resulting in agglomeration or clumping.
  • the lateral acoustic radiation force component overcomes fluid drag, which permits clumps of particles to continually grow and then drop out of the mixture due to gravity.
  • a drop in drag per particle as the particle cluster increases in size and a drop in acoustic radiation force per particle as the particle cluster grows in size may be considered together or independently in the operation of the acoustic separator device.
  • the lateral force component and the axial force component of the multi-dimensional acoustic standing wave are of the same order of magnitude.
  • the axial force may have a different value than the lateral force, e.g. be weaker or stronger, or may be equal or equivalent, but the lateral force of a multi-dimensional acoustic standing wave is greater than the lateral force of a planar standing wave, sometimes by two orders of magnitude or more.
  • FIG. 4 a schematic illustration of a system that uses the acoustophoretic device is shown. This system was also used to test the performance of the acoustophoretic device.
  • a transducer module 190 controlled the mechanical output of a transducer used in an acoustic filtration device 100 to create a multi-dimensional acoustic standing wave at high frequencies (1 -3 MHz) and high amplitude (up to 100 V).
  • the resonator section of the acoustic filtration device i.e., defined by the transducer- reflector pair in which the acoustic standing wave is generated
  • the transducer control module 190 periodically scans the adjacent frequency region and switches for the optimal frequency under the current conditions.
  • Peristaltic pumps of the pump module 191 are used to independently control the flows of the feed from the inflow reservoir 192 and the buffer reservoir 193 (i.e., at the inlet) and RBC collection (i.e., at the concentrate outlet).
  • the output from the filtrate outlet of the acoustic device 100 is collected in filtrate reservoir 194.
  • a fraction collector was used to collect the eluted material during the operation at known times and characterize the acoustic system performance at different stages of the operation. The tests were performed with porcine blood purchased from Hemostat Laboratories, CA.
  • FIG. 5 illustrates the fluid flow path through the acoustic filtration system (e.g. , the acoustophoretic device of FIG. 1 ).
  • Blood entered the device at the inlet thereof with a flow rate V in and continued into the flow chamber and through the acoustic standing wave.
  • the filtrate i.e. , clarified fluid
  • the concentrated cells exit the device at a flow rate V c .
  • the system performance was characterized over a wide range of flow rates.
  • FIG. 6B show the system performance at different combinations of the feed flow rate (V in ) and of the ratio of the flow rates of the filtrate outlet (V f ) and the concentrate outlet (V c ).
  • FIG. 6A presents the red blood cell collection percentage of the device
  • RBC concentration factor is the ratio of RBC concentration for the concentrate outlet flow relative to that of the input flow; for example, blood flowing in at a hematocrit of 10% (i.e. , 10-fold diluted blood) that was reconstituted to a hematocrit of 20% (i.e. , 5-fold diluted blood) at the concentrate outlet would yield a concentration factor of 2.
  • the highest concentration of RBCs in the collector was achieved at the highest elution flow ratios, where the same amount of the cells was eluted in smaller volume.
  • Table 2 Summary of Varying Dilution Results (10 mL/min inflow and ratio of 4)
  • the concentrate outlet draw was set to 1 mL/min, resulting in a flow of 15 mL/min into the outflow reservoir of the system.
  • Visual observations were made using a Proscope HR USB camera from Bodelin (Lake Oswego, OR) to document lipid aggregation on the top polycarbonate window.
  • Complete blood counts were obtained using a VetScan HMS hematology analyzer from Abaxis Co. (Union City, CA).
  • This step was introduced because systems for surgical blood treatment include a similar filter to remove clots and bone fragments, which are typical admixtures in the blood, collected from the surgical field, and thus contaminate the RBC fraction either with centrifugal or acoustic method.
  • the filter removed large particles that constitute most of the fat after extensive homogenization (the particles are expected to be larger in real surgery); less than 10% of the initial load ⁇ 0.02% total content) remained in the diluted blood sample (compare images A and B in FIG. 7).
  • the final mixture was sent into the acoustophoretic device. Once collected, the lipids were dried and weighed. Weighing was used because radioactive labels could not be used due to the lack of laboratories still practicing the same. Fluorescence-based analysis cannot be used with blood products because of background interference, and fluorescence is also not a quantitative method.
  • FIGS. 7A-7E illustrate a lipid image analysis at 40x magnification.
  • the leftmost image in the top row (FIG. 7A) shows lipid particles in saline immediately after spike.
  • the middle image in the top row (FIG. 7B) shows the lipid particles in saline after filtration through a physical filter.
  • the rightmost image in the top row (FIG. 7C) shows the lipid particles in saline after undergoing acoustic filtration according to the present disclosure.
  • the left side image in the bottom row (FIG. 7D) shows the lipid particles in saline after agglomerating and rising to a lipid collection trap at the top of a flow chamber.
  • the right side image in the bottom row (FIG. 7E) shows a top view of the lipid collection trap after filtration of the lipid particles according to the present disclosure.
  • Treatment by the acoustic standing wave system produced two effects. First, an additional part of the lipids was removed (see FIG. 7D and FIG. 7E). These particles were larger than those in the injected spike due to acoustics-induced clumping. Second, although the sizes of the particles that penetrated through the system and were found in the filtrate were similar to the sizes of the particles right after the LipiGuard filtration, the proportion of larger particles was smaller after acoustic treatment. This effect is difficult to see in FIG. 7B and FIG. 7C, but was noticeable after visual comparison of multiple frames.
  • Quantitation of the lipid content gives 60 ⁇ 5 mg, 65 ⁇ 15 mg, and 150 ⁇ 25 mg in the fraction extracted from the lipid collection trap, from the resonator volume, and from the filtrate, respectively. In total, this constitutes 275 ⁇ 45 mg of lipids, which coincides within the error with the spiked load of 250 ⁇ 20 mg. On the one hand, this gives no detectable lipid load in the fraction collected through the concentrate outlet (neither by subtraction nor by the direct measurement). On the other hand, about half of the lipid load passed through the acoustic filter and collected in the filtrate outlet. However, this fraction is mostly void of particles larger than the size of cells; therefore, the remaining lipid particles are too small to cause microemboli. Most of the particles with sizes in the range of 10 to 40 microns were acoustically removed.
  • FIG. 8 is a graph showing the platelet aggregation of the blood after processing in the acoustophoretic system and the platelet aggregation of unprocessed blood. As can be seen in the date in FIG. 8, no discernable evidence of aggregation / coagulation was found, which shows that the acoustic energy used did not have a deleterious effect on the blood components.
  • Porcine ELISA kits were used to determine levels of various biological markers in processed and unprocessed blood. Five ELISA kits were used for this study: (1 ) Porcine Haptoglobin ELISA Kit from GenWay Biotech (San Diego, CA); (2) Porcine LDH ELISA Kit from Novateinbio (Woburn, MA); (3) Porcine D-Dimer ELISA Kit from US Biological (Salem, MA); (4) Porcine IL-6 ELISA Kit from Sigma Aldrich (St. Louis, MO); and (5) Porcine TNF-a ELISA Kit from Fisher Scientific (Waltham, MA).
  • FIG. 9A shows the D-Dimer formation of the acoustically separated blood versus the control blood.
  • the ELISA measurement demonstrated no significant change in D-Dimer levels, evidencing that the acoustic filtration did not cause thrombus formation.
  • Potential activation of the complement pathway was also examined by exploring IL-6 and TNF-a release.
  • FIG. 9B presents the results, which show that in comparison with the non-acoustically processed blood (i.e., the control blood), there was a decrease of 79% in the IL-6 concentration and 87% in the TNF-a concentration. These results signify that no inflammatory activation occurred due to the acoustic capture of the cells.
  • Lactate dehydrogenase and haptoglobin ELISAs were also performed on recombined treated blood (i.e., AWS processed blood) and compared to non-treated blood (i.e., control blood). These tests were performed to ensure that the acoustic energy was not causing the red blood cells to rupture. The results are presented in FIG. 10, which shows that there was a slight increase of 15% in haptoglobin levels, while LDH levels decreased by 2.5%. Thus, neither measurement demonstrated hemolysis was occurring after acoustic processing, which was consistent with a lack of hemolysis upon microscopic inspection of the RBCs (data not shown). Again, the results of these ELISAs are also presented in Table 3 below.
  • the amount of blood removed was no more than ⁇ 15% of the animals' total blood volume, thereby preventing shock and hemodynamic instability.
  • the AWS processing occurred in two steps to get fluid back to the animal as quickly as possible.
  • 125 mL of whole blood was diluted with 875 mL of normal saline to create a 7: 1 saline to blood dilution. This dilution was then processed through the acoustophoretic system.
  • the collected 200 ml_ blood product was transfused back to the animal, while a second portion of the blood, which was diluted at the same ratio, was processed. A total of 400 mL of blood product was transfused back into each animal.
  • FIG. 11 A presents the pigs' SBP levels
  • FIG. 11 B presents the pigs' MAP levels.
  • SBP and MAP decreased soon after exsanguination in both animals.
  • a rise in both is seen prior to the transfusions, which is secondary to the animals' own compensatory drive.
  • FIG. 11 A and FIG. 11 B show, respectively, that the animals' SBP and MAP were not significantly affected by the acoustically processed blood versus the control.
  • FIG. 12 an illustrative embodiment of an acoustophoretic system 1200 is depicted.
  • the system generally includes an acoustophoretic device according to the present disclosure, such as acoustophoretic device 100 depicted in FIG. 1 and FIG. 2.
  • an acoustophoretic device according to the present disclosure, such as acoustophoretic device 100 depicted in FIG. 1 and FIG. 2.
  • the portability of the system 1200 can be achieved by making the acoustophoretic device battery- powered, such that in emergency or force majeure situations, patient treatment can be performed under field conditions void of electrical power or ability to transport heavy equipment to the point of care.
  • the system 1200 can be a platform-based system, such as a system housed within a portable briefcase 1202 as is depicted in FIG. 12. It is further contemplated that all components of the system in contact with blood and its products will be united into a single disposable unit, including input and output lines integrated with the acoustic resonator, and replaced as a whole between preparations of different blood batches.
  • the disposable units will be sealed and sterilized to prevent contamination and infections and will be installed in only one way to prevent human error. Additionally, the system performance may be enhanced by using different disposable assemblies optimized for specific procedures (e.g., lipid extraction, blood cell isolation, cell washing, blood banking).
  • the devices can include a container for collecting the isolated materials (e.g., red blood cells, lipids).
  • the container collecting the product after processing will be designed to be detachable once the operation is complete, automatically sealed upon removal to maintain the sterility of the material, and usable at temperatures as low as -80 °C.
  • the container 1204 is a flexible bag.
  • a separate flexible bag is also used as the input reservoir 1206 of blood.
  • the ultrasonic transducer-reflector pair can be sterile and disposable.
  • the transducer- reflector pair can be integrated as part of the disposable assembly.
  • the advantages of such a design include the most efficient acoustic performance by coupling the transducer with, for example, a molded flow chamber of a Class 6 material and the means to isolate the transducer surface from the contact with blood.
  • Another alternative option is to develop a flow chamber that will be an insert into a transducer-reflector assembly. In this case, the introduction of additional layers will decrease the acoustic performance, but this option is cheaper than the first option, which is a major driver for disposable applications.
  • the total volume of suction blood to be filtered during a bypass surgery can approach 1 liter to 1 .5 liters, which can be collected within 45 minutes.
  • the systems and devices disclosed herein are capable of processing this amount.
  • these systems and device can handle about 20 mL/min to about 30 mL/min, and up to as high as 2 L/hour or more, of whole undiluted blood flow (i.e., up to about 20 L/hour of 10-fold diluted blood flow).
  • This blood is not typically re-transfused to the patient right away, but rather returned at the end of the operation.
  • RBC concentration for transfusion, although as low as 50% can be acceptable.
  • Normal RBC concentration is 40-45% by volume.
  • the systems and devices of the present disclosure are capable of achieving 32-36% RBC (80% of normal hematocrit) in concentrates intended for transfusion.
  • the RBC concentration is less important, because the product will be subjected to additional washing that accompanies deglycerolization; the RBC concentration can be increased at this stage the same way it will be done for a transfusion product.
  • RBCs During prolonged storage at 4 °C, RBC concentrates acquire 'storage lesions.' The suspending solvent composition changes due to RBC metabolism and degradation of some of the cells (e.g., concentrations of ammonia, phosphate, potassium, and free hemoglobin increase as well as the solvent's acidity). RBCs also experience morphological shape changes: their membranes stiffen, the cells change shape, become stickier, and more tightly bind oxygen. These changes, which may impair clinical outcomes after transfusion, can be corrected to a large extent by washing RBCs in proper solvents. Also, washing out-of-date (i.e., 1 -4 weeks after their expiration dates) RBCs with a cell saver device makes them usable and safe for a patient.
  • the suspending solvent composition changes due to RBC metabolism and degradation of some of the cells (e.g., concentrations of ammonia, phosphate, potassium, and free hemoglobin increase as well as the solvent's acidity).
  • RBCs also experience morphological shape
  • RBC concentrates can also be stored at -80°C, and can be preserved for decades at this temperature. Donor blood can be stored at 4 °C until the expiration date, and then cryopreserved, where it will be still viable for decades. Typically, only RBCs are frozen.
  • Preparation of blood for deep freezing or for transfusion after thawing can include the addition or removal of a cryoprotectant (glycerol). These operations also involve washing the RBCs in an appropriate solvent, and the recovery achieves 94%. The quality of the recovered RBCs primarily depends on the deglycerolization washing process, on the biologic variation among RBC units, and on the pre-freeze and post-thaw storage times.
  • a cryoprotectant glycerol
  • the first option is to dilute the whole blood with a washing solvent.
  • the diluted blood is then sent through an acoustic filtration device to concentrate the red blood cells in the now-diluted blood in accordance with the methods already disclosed herein.
  • a second option is to first send the whole blood through the acoustic filtration device to trap red blood cells within the acoustic standing wave (without the RBCs concentrating and falling out of the standing wave).
  • the washing solvent is then sent through the flow chamber to wash the RBCs.
  • An intermediate approach is to combine the flows of undiluted whole blood and the washing solvent into a single flow, which can be flowed through the flow chamber at a flow rate of at least 4.5 mL/min, and then performing the RBC separation in accordance with the methods already disclosed herein.
  • This intermediate approach is depicted in FIG. 4.
  • washing solvents include water and saline.
  • Integration of a washing option with the systems and devices of the present disclosure can include the presence of a subsystem to inject different solvents in a controlled way into undiluted whole blood.
  • a single system/device can be used for blood, in addition to the various other techniques discussed herein.
  • the systems/devices are capable of injecting and mixing aqueous solvents as well as high concentration glycerol solvents. After the procedures, the blood components may be thoroughly tested with biochemical assays.
  • the systems and devices of the present disclosure may also be optimized for platelet isolation from blood. This function may involve several centrifugation steps in conventional machines, because of the small difference in properties between RBCs and platelets. However, using ASW technology, several simpler options are available.
  • the ASW systems/devices may employ different acoustic frequencies to enhance selectivity in different scale domains.
  • acoustic force depends on the size of the cells (see the equation for acoustic radiation force above), larger cells are held more strongly than smaller cells at a fixed frequency. Therefore, this technique can be used to isolate platelets (2-3 pm), which are smaller than RBCs or leukocytes (6-8 pm and 10-15 pm, respectively).
  • An ASW system will perform better in prolonged or repeated processes, because of its minimal (if any) influence on the cell vitality. This is especially important in the treatment of platelets to avoid their activation. Because of minimal acoustic damage, multiple cycles can be implemented to improve separation.
  • a second option for platelet isolation is to employ specialty fluidics.
  • acoustic and hydrodynamic forces are proportional to the third and second power of particle radius, respectively.
  • variation of the transducer power in combination with the flow rate can be used for separation.
  • a third option is to introduce macroscopic changes using biological differences, which in turn will modify susceptibility to acoustic force.
  • dead and live cells have different membrane permeability. Therefore, manipulation with osmotic pressure may introduce differences in sizes between the dead and live cells. Red blood cells accumulate organic compounds that intercalate the membrane and change its rigidity as well as the overall size and shape of erythrocytes. This difference can be also exploited for fractionation.
  • FIG. 13 A diagrammatic representation of an acoustic chamber for removing lipids or other lighter-than-blood material is shown in FIG. 13. Excitation frequencies typically in the range from hundreds of kHz to 10s of MHz are applied by transducer 10. One or more standing waves are created between the transducer 10 and the reflector 11. Incoming blood containing blood components enters at inlet 12. Particles (e.g., lipids) are trapped in standing waves at the pressure anti-nodes 14 where they agglomerate, aggregate, clump, or coalesce, and, in the case of buoyant material, float to the surface and are discharged via a lipid collection trap 16 located above the flow path and above the acoustic standing wave. Clarified fluid (e.g., blood) is discharged at filtrate outlet 18.
  • the acoustophoretic separation technology can accomplish multi-component particle separation without any fouling at a much reduced cost.
  • FIG. 14 A diagrammatic representation of an acoustic chamber for removing blood cells or other heavier-than-blood material is shown in FIG. 14. Excitation frequencies typically in the range from hundreds of kHz to 10s of MHz are applied by transducer 10. One or more standing waves are created between the transducer 10 and the reflector 11. Incoming blood enters through inlet 13. Particles (e.g., blood cells) are trapped in standing waves at the pressure nodes 15 where they agglomerate, aggregate, clump, or coalesce, and, in the case of heavier material, sink to the bottom and are discharged via a concentrate outlet 17 located below the flow path and below the acoustic standing wave. Clarified fluid (e.g., blood) is discharged at filtrate outlet 18.
  • Clarified fluid e.g., blood
  • the ultrasonic transducer and reflector are located on opposite sides of the acoustic chamber. In this way, one or more acoustic standing waves are created between the ultrasonic transducer and reflector.
  • the multi-dimensional acoustic standing wave used for particle collection is obtained by driving an ultrasonic transducer at a frequency that both generates the acoustic standing wave and excites a fundamental 3D vibration mode of the transducer crystal. Perturbation of the piezoelectric crystal in an ultrasonic transducer in a multimode fashion allows for generation of a multidimensional acoustic standing wave.
  • a piezoelectric crystal can be specifically designed to deform in a multimode fashion at designed frequencies, allowing for generation of a multi-dimensional acoustic standing wave.
  • the multi-dimensional acoustic standing wave may be generated by distinct modes of the piezoelectric crystal such as a 3x3 mode that would generate multidimensional acoustic standing waves.
  • a multitude of multidimensional acoustic standing waves may also be generated by allowing the piezoelectric crystal to vibrate through many different mode shapes.
  • the crystal would excite multiple modes such as a 0x0 mode (i.e. a piston mode) to a 1x1 , 2x2, 1x3, 3x1 , 3x3, and other higher order modes and then cycle back through the lower modes of the crystal (not necessarily in straight order).
  • This switching or dithering of the crystal between modes allows for various multidimensional wave shapes, along with a single piston mode shape to be generated over a designated time.
  • the transducers use a piezoelectric crystal, usually made of PZT-8 (lead zirconate titanate). Such crystals may have a 1 inch diameter and a nominal 2 MHz resonance frequency, and may also be of a larger size.
  • Each ultrasonic transducer module can have only one crystal, or can have multiple crystals that each act as a separate ultrasonic transducer and are either controlled by one or multiple amplifiers.
  • the crystals can be square, rectangular, irregular polygon, or generally of any arbitrary shape.
  • the transducer(s) is/are used to create a pressure field that generates forces of the same order of magnitude both orthogonal to the standing wave direction (lateral) and in the standing wave direction (axial).
  • FIG. 15 is a cross-sectional diagram of a conventional ultrasonic transducer.
  • This transducer has a wear plate 50 at a bottom end, epoxy layer 52, ceramic crystal 54 (made of, e.g. PZT), an epoxy layer 56, and a backing layer 58.
  • On either side of the ceramic crystal there is an electrode: a positive electrode 61 and a negative electrode 63.
  • the epoxy layer 56 attaches backing layer 58 to the crystal 54.
  • the entire assembly is contained in a housing 60 which may be made out of, for example, aluminum.
  • An electrical adapter 62 provides connection for wires to pass through the housing and connect to leads (not shown) which attach to the crystal 54.
  • backing layers are designed to add damping and to create a broadband transducer with uniform displacement across a wide range of frequency and are designed to suppress excitation at particular vibrational eigenmodes.
  • Wear plates are usually designed as impedance transformers to better match the characteristic impedance of the medium into which the transducer radiates.
  • FIG. 16 is a cross-sectional view of an ultrasonic transducer 81 of the present disclosure.
  • Transducer 81 is shaped as a disc or a plate, and has an aluminum housing 82.
  • the piezoelectric crystal is a mass of perovskite ceramic crystals, each consisting of a small, tetravalent metal ion, usually titanium or zirconium, in a lattice of larger, divalent metal ions, usually lead or barium, and 02- ions.
  • a PZT (lead zirconate titanate) crystal 86 defines the bottom end of the transducer, and is exposed from the exterior of the housing.
  • the crystal is supported on its perimeter by a small elastic layer 98, e.g. silicone or similar material, located between the crystal and the housing. Put another way, no wear layer is present.
  • the crystal is an irregular polygon, and in further embodiments is an asymmetrical irregular polygon.
  • Screws 88 attach an aluminum top plate 82a of the housing to the body 82b of the housing via threads.
  • the top plate includes a connector 84 for powering the transducer.
  • the top surface of the PZT crystal 86 is connected to a positive electrode 90 and a negative electrode 92, which are separated by an insulating material 94.
  • the electrodes can be made from any conductive material, such as silver or nickel. Electrical power is provided to the PZT crystal 86 through the electrodes on the crystal. Note that the crystal 86 has no backing layer or epoxy layer. Put another way, there is an air gap 87 in the transducer between aluminum top plate 82a and the crystal 86 (i.e. the air gap is completely empty).
  • a minimal backing 58 and/or wear plate 50 may be provided in some embodiments, as seen in FIG. 17.
  • the transducer design can affect performance of the system.
  • a typical transducer is a layered structure with the ceramic crystal bonded to a backing layer and a wear plate. Because the transducer is loaded with the high mechanical impedance presented by the standing wave, the traditional design guidelines for wear plates, e.g., half wavelength thickness for standing wave applications or quarter wavelength thickness for radiation applications, and manufacturing methods may not be appropriate. Rather, in one embodiment of the present disclosure the transducers, there is no wear plate or backing, allowing the crystal to vibrate in one of its eigenmodes (i.e. near eigenfrequency) with a high Q-factor. The vibrating ceramic crystal/disk is directly exposed to the fluid flowing through the flow chamber.
  • Removing the backing also permits the ceramic crystal to vibrate at higher order modes of vibration with little damping (e.g. higher order modal displacement).
  • a transducer comprising a crystal with a backing
  • the crystal vibrates with a more uniform displacement, like a piston.
  • Removing the backing allows the crystal to vibrate in a non-uniform displacement mode.
  • the higher order the mode shape of the crystal the more nodal lines the crystal may have.
  • the higher order modal displacement of the crystal creates more trapping lines, although the correlation of trapping line to node is not necessarily one to one, and driving the crystal at a higher frequency will not necessarily produce more trapping lines.
  • the crystal may have a backing that minimally affects the Q-factor of the crystal (e.g. less than 5%).
  • the backing may be made of a substantially acoustically transparent material such as balsa wood, foam, or cork which allows the crystal to vibrate in a higher order mode shape and maintains a high Q-factor while still providing some mechanical support for the crystal.
  • the backing layer may be a solid, or may be a lattice having holes through the layer, such that the lattice follows the nodes of the vibrating crystal in a particular higher order vibration mode, providing support at node locations while allowing the rest of the crystal to vibrate freely.
  • the goal of the lattice work or acoustically transparent material is to provide support without lowering the Q-factor of the crystal or interfering with the excitation of a particular mode shape.
  • Placing the crystal in direct contact with the fluid also contributes to the high Q-factor by avoiding the dampening and energy absorption effects of the epoxy layer and the wear plate.
  • Other embodiments may have wear plates or a wear surface to prevent the PZT, which contains lead, contacting the host fluid.
  • Such wear material may be desirable in, for example, biological applications such as separating blood. Such applications might use a wear layer such as chrome, electrolytic nickel, or electroless nickel.
  • Chemical vapor deposition could also be used to apply a layer of poly(p-xylylene) (e.g. Parylene) or other polymers or polymer films.
  • Organic and biocompatible coatings such as silicone or polyurethane are also usable as a wear surface.
  • FIG. 18 is a log-log graph (logarithmic y-axis, logarithmic x-axis) that shows the scaling of the acoustic radiation force, fluid drag force, and buoyancy force with particle radius, and provides an explanation for the separation of particles using acoustic radiation forces.
  • the buoyancy force is a particle volume dependent force, and is therefore negligible for particle sizes on the order of micron, but grows, and becomes significant for particle sizes on the order of hundreds of microns.
  • the fluid drag force (Stokes drag force) scales linearly with fluid velocity, and therefore typically exceeds the buoyancy force for micron sized particles, but is negligible for larger sized particles on the order of hundreds of microns.
  • the acoustic radiation force scaling is different.
  • Gor'kov's equation is accurate and the acoustic trapping force scales with the volume of the particle.
  • the acoustic radiation force no longer increases with the cube of the particle radius, and will rapidly vanish at a certain critical particle size.
  • the radiation force increases again in magnitude but with opposite phase (not shown in the graph). This pattern repeats for increasing particle sizes.
  • the particles cluster shield each other from the fluid flow and reduce the overall drag of the cluster.
  • the acoustic radiation force reflects off the cluster, such that the net acoustic radiation force decreases per unit volume.
  • the acoustic lateral forces on the particles may be different than the drag forces for the clusters to remain stationary and grow in size.
  • the acoustic lateral forces may be larger than the drag forces to permit particles to be trapped, cluster and grow in size.
  • FIG. 18 explains how small particles can be trapped continuously in a standing wave, grow into larger particles or clumps, and then eventually will rise or settle out because of increased buoyancy force.
  • the size, shape, and thickness of the transducer determine the transducer displacement at different frequencies of excitation, which in turn affects particle separation efficiency.
  • Higher order modal displacements generate three-dimensional acoustic standing waves with strong gradients in the acoustic field in all directions, thereby creating equally strong acoustic radiation forces in all directions, leading to multiple trapping lines, where the number of trapping lines correlate with the particular mode shape of the transducer.
  • FIG. 19 shows the measured electrical impedance amplitude of the transducer as a function of frequency in the vicinity of the 2.2 MHz transducer resonance.
  • the minima in the transducer electrical impedance correspond to acoustic resonances of a water column and represent potential frequencies for operation.
  • Numerical modeling has indicated that the transducer displacement profile varies significantly at these acoustic resonance frequencies, and thereby directly affects the acoustic standing wave and resulting trapping force. Since the transducer operates near its thickness resonance, the displacements of the electrode surfaces are essentially out of phase.
  • the typical displacement of the transducer electrodes is not uniform and varies depending on frequency of excitation. Higher order transducer displacement patterns result in higher trapping forces and multiple stable trapping lines for the captured particles.
  • FIG. 20B shows an isometric view of the system in which the trapping line locations are being determined.
  • FIG. 20C is a view of the system as it appears when looking down the inlet, along arrow 814.
  • FIG. 20D is a view of the system as it appears when looking directly at the transducer face, along arrow 816.
  • excitation frequency clearly determines the number of trapping lines, which vary from a single trapping line at the excitation frequency of acoustic resonance 5 and 9, to nine trapping lines for acoustic resonance frequency 4. At other excitation frequencies four or five trapping lines are observed.
  • Different displacement profiles of the transducer can produce different (more) trapping lines in the standing waves, with more gradients in displacement profile generally creating higher trapping forces and more trapping lines. It is noted that although the different trapping line profiles shown in FIG. 20A were obtained at the frequencies shown in FIG. 19, these trapping line profiles can also be obtained at different frequencies.
  • FIG. 20A shows the different crystal vibration modes possible by driving the crystal to vibrate at different fundamental frequencies of vibration.
  • the 3D mode of vibration of the crystal is carried by the acoustic standing wave across the fluid in the chamber all the way to the reflector and back.
  • the resulting multi-dimensional standing wave can be thought of as containing two components.
  • the first component is a planar out-of-plane motion component (uniform displacement across crystal surface) of the crystal that generates a standing wave
  • the second component is a displacement amplitude variation with peaks and valleys occurring in both lateral directions of the crystal surface.
  • Three-dimensional force gradients are generated by the standing wave.

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Abstract

La présente invention concerne des dispositifs acoustophorétiques. Les dispositifs comprennent une chambre d'écoulement, un transducteur à ultrasons, un réflecteur, une entrée, une sortie de filtrat, une sortie de concentré, et éventuellement un piège de collecte de lipide. Le transducteur à ultrasons et le réflecteur créent une onde stationnaire acoustique multi-dimensionnelle dans la chambre d'écoulement qui piège et sépare les globules rouges et/ou les lipides du sang. Les globules rouges concentrés peuvent être récupérés par l'intermédiaire de la sortie de concentré, les lipides peut être récupérés par l'intermédiaire du piège de collecte de lipide, et le sang restant peut être récupéré par l'intermédiaire de la sortie de filtrat. L'invention concerne également des procédés de séparation de composants du sang (p. ex. globules rouges, lipides, plaquettes, globules blancs) du sang. Les globules rouges peuvent subir un lavage avec un solvant afin d'éliminer les impuretés non désirées. Des agents cryoprotecteurs peuvent être ajoutés ou retirés du sang.
PCT/US2016/050415 2015-09-04 2016-09-06 Procédés et dispositifs de séparation acoustique du sang Ceased WO2017041102A1 (fr)

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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017192760A1 (fr) * 2016-05-03 2017-11-09 Flodesign Sonics, Inc. Lavage, concentration et séparation de cellules thérapeutiques par acoustophorèse
US10308928B2 (en) 2013-09-13 2019-06-04 Flodesign Sonics, Inc. System for generating high concentration factors for low cell density suspensions
US10662402B2 (en) 2012-03-15 2020-05-26 Flodesign Sonics, Inc. Acoustic perfusion devices
US10689609B2 (en) 2012-03-15 2020-06-23 Flodesign Sonics, Inc. Acoustic bioreactor processes
US10704021B2 (en) 2012-03-15 2020-07-07 Flodesign Sonics, Inc. Acoustic perfusion devices
US10724029B2 (en) 2012-03-15 2020-07-28 Flodesign Sonics, Inc. Acoustophoretic separation technology using multi-dimensional standing waves
US10737953B2 (en) 2012-04-20 2020-08-11 Flodesign Sonics, Inc. Acoustophoretic method for use in bioreactors
US10785574B2 (en) 2017-12-14 2020-09-22 Flodesign Sonics, Inc. Acoustic transducer driver and controller
CN111773177A (zh) * 2020-07-16 2020-10-16 南京大学 一种利用声辐射力实现药物粒子定点释放方法
US10814253B2 (en) 2014-07-02 2020-10-27 Flodesign Sonics, Inc. Large scale acoustic separation device
CN112055618A (zh) * 2018-05-01 2020-12-08 精密种植有限责任公司 用于测试的分析盒以及相关方法
US20210045639A1 (en) * 2017-05-16 2021-02-18 Heartware, Inc. Intra ventricular ambulatory implantable pv loop system
US10947493B2 (en) 2012-03-15 2021-03-16 Flodesign Sonics, Inc. Acoustic perfusion devices
US10967298B2 (en) 2012-03-15 2021-04-06 Flodesign Sonics, Inc. Driver and control for variable impedence load
US10975368B2 (en) 2014-01-08 2021-04-13 Flodesign Sonics, Inc. Acoustophoresis device with dual acoustophoretic chamber
US11007457B2 (en) 2012-03-15 2021-05-18 Flodesign Sonics, Inc. Electronic configuration and control for acoustic standing wave generation
US11021699B2 (en) 2015-04-29 2021-06-01 FioDesign Sonics, Inc. Separation using angled acoustic waves
US11085035B2 (en) 2016-05-03 2021-08-10 Flodesign Sonics, Inc. Therapeutic cell washing, concentration, and separation utilizing acoustophoresis
US11214789B2 (en) 2016-05-03 2022-01-04 Flodesign Sonics, Inc. Concentration and washing of particles with acoustics
US11377651B2 (en) 2016-10-19 2022-07-05 Flodesign Sonics, Inc. Cell therapy processes utilizing acoustophoresis
US11420136B2 (en) 2016-10-19 2022-08-23 Flodesign Sonics, Inc. Affinity cell extraction by acoustics
US11459540B2 (en) 2015-07-28 2022-10-04 Flodesign Sonics, Inc. Expanded bed affinity selection
US11474085B2 (en) 2015-07-28 2022-10-18 Flodesign Sonics, Inc. Expanded bed affinity selection
US11708572B2 (en) 2015-04-29 2023-07-25 Flodesign Sonics, Inc. Acoustic cell separation techniques and processes

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013159014A1 (fr) * 2012-04-20 2013-10-24 Flodesign Sonics Inc. Séparation acoustophorétique de particules lipidiques provenant de globules rouges
WO2014055219A2 (fr) * 2012-10-02 2014-04-10 Flodesign Sonics, Inc. Technologie de séparation acoustophorétique utilisant des ondes stationnaires multidimensionnelles
US9228183B2 (en) 2012-03-15 2016-01-05 Flodesign Sonics, Inc. Acoustophoretic separation technology using multi-dimensional standing waves

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9228183B2 (en) 2012-03-15 2016-01-05 Flodesign Sonics, Inc. Acoustophoretic separation technology using multi-dimensional standing waves
WO2013159014A1 (fr) * 2012-04-20 2013-10-24 Flodesign Sonics Inc. Séparation acoustophorétique de particules lipidiques provenant de globules rouges
WO2014055219A2 (fr) * 2012-10-02 2014-04-10 Flodesign Sonics, Inc. Technologie de séparation acoustophorétique utilisant des ondes stationnaires multidimensionnelles

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BART LIPKENS ET AL: "Macro-scale acoustophoretic separation of lipid particles from red blood cells", THE JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA, vol. 133, 2 June 2013 (2013-06-02), New York, NY, US, pages 045017, XP055162509, ISSN: 0001-4966, DOI: 10.1121/1.4799371 *
EVGENIA ZABOLOTSKAYA, AIP CONFERENCE PROCEEDINGS, vol. 1474, no. 1, 2012, pages 255 - 258

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10724029B2 (en) 2012-03-15 2020-07-28 Flodesign Sonics, Inc. Acoustophoretic separation technology using multi-dimensional standing waves
US11007457B2 (en) 2012-03-15 2021-05-18 Flodesign Sonics, Inc. Electronic configuration and control for acoustic standing wave generation
US10967298B2 (en) 2012-03-15 2021-04-06 Flodesign Sonics, Inc. Driver and control for variable impedence load
US10662402B2 (en) 2012-03-15 2020-05-26 Flodesign Sonics, Inc. Acoustic perfusion devices
US10689609B2 (en) 2012-03-15 2020-06-23 Flodesign Sonics, Inc. Acoustic bioreactor processes
US10704021B2 (en) 2012-03-15 2020-07-07 Flodesign Sonics, Inc. Acoustic perfusion devices
US10947493B2 (en) 2012-03-15 2021-03-16 Flodesign Sonics, Inc. Acoustic perfusion devices
US10737953B2 (en) 2012-04-20 2020-08-11 Flodesign Sonics, Inc. Acoustophoretic method for use in bioreactors
US10308928B2 (en) 2013-09-13 2019-06-04 Flodesign Sonics, Inc. System for generating high concentration factors for low cell density suspensions
US10975368B2 (en) 2014-01-08 2021-04-13 Flodesign Sonics, Inc. Acoustophoresis device with dual acoustophoretic chamber
US10814253B2 (en) 2014-07-02 2020-10-27 Flodesign Sonics, Inc. Large scale acoustic separation device
US11021699B2 (en) 2015-04-29 2021-06-01 FioDesign Sonics, Inc. Separation using angled acoustic waves
US11708572B2 (en) 2015-04-29 2023-07-25 Flodesign Sonics, Inc. Acoustic cell separation techniques and processes
US11459540B2 (en) 2015-07-28 2022-10-04 Flodesign Sonics, Inc. Expanded bed affinity selection
US11474085B2 (en) 2015-07-28 2022-10-18 Flodesign Sonics, Inc. Expanded bed affinity selection
US11085035B2 (en) 2016-05-03 2021-08-10 Flodesign Sonics, Inc. Therapeutic cell washing, concentration, and separation utilizing acoustophoresis
WO2017192760A1 (fr) * 2016-05-03 2017-11-09 Flodesign Sonics, Inc. Lavage, concentration et séparation de cellules thérapeutiques par acoustophorèse
US11214789B2 (en) 2016-05-03 2022-01-04 Flodesign Sonics, Inc. Concentration and washing of particles with acoustics
US10640760B2 (en) 2016-05-03 2020-05-05 Flodesign Sonics, Inc. Therapeutic cell washing, concentration, and separation utilizing acoustophoresis
US11377651B2 (en) 2016-10-19 2022-07-05 Flodesign Sonics, Inc. Cell therapy processes utilizing acoustophoresis
US11420136B2 (en) 2016-10-19 2022-08-23 Flodesign Sonics, Inc. Affinity cell extraction by acoustics
US20210045639A1 (en) * 2017-05-16 2021-02-18 Heartware, Inc. Intra ventricular ambulatory implantable pv loop system
US11826127B2 (en) * 2017-05-16 2023-11-28 Heartware, Inc. Intra ventricular ambulatory implantable PV loop system
US10785574B2 (en) 2017-12-14 2020-09-22 Flodesign Sonics, Inc. Acoustic transducer driver and controller
CN112055618A (zh) * 2018-05-01 2020-12-08 精密种植有限责任公司 用于测试的分析盒以及相关方法
CN112055618B (zh) * 2018-05-01 2022-10-14 精密种植有限责任公司 用于测试的分析盒以及相关方法
CN111773177A (zh) * 2020-07-16 2020-10-16 南京大学 一种利用声辐射力实现药物粒子定点释放方法

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