"High-Efficiency Separation and Manipulation of Particles and Cells in Microfluidic Device Using Surface Acoustic Waves at an Oblique Angle" in Patent Application Approval Process
This patent application is assigned to
The following quote was obtained by the news editors from the background information supplied by the inventors: "Efficient separation of suspended particles and cells is essential to many fundamental biomedical studies such as cancer cell detection and drug screening. The most popular methods for cell separation in the life science laboratory so far are the centrifugal methods, which are capable of separating cells with differences in size and density. Another industrial and clinical standard for high quality cell separation is a FACS (fluorescence activated cell sorter). The FACS technology is performed in a sheath flow mode where cells are focused in the center of buffer and then pass through a laser beam for high speed and precise optical detection. The cells can be separated by a downstream electric field triggered by the optical signal. In the past years, fundamental advances in the lab-on-a-chip technologies have driven development of new approaches to cell separation. Examples include magnetic, hydrodynamic, optical lattice, electrophoresis/dielectrophoretic (DEP), and acoustic methods.
"The magnetic method starts with labeling cells of interest with magnetic markers. Then an external magnetic field is applied to the sample, leading to the separation of labeled cells from the rest. The labeling step required for magnetic methods usually increases cost and processing time, and may also have a negative effect on the cells of interest. The hydrodynamic methods usually involve high flow speed (inertial force based method) or asymmetric obstacles inside the channel (deterministic lateral displacement). These methods permit continuous operation without requiring additional labeling or external forces. However, the channel obstacles in the channel may exert high mechanical stress on cells and lead to low throughput. The optical lattice method provides a unique separation approach which can separate particles with different optical properties. However, this approach has two potential shortcomings: 1) the potential laser-induced heating, the formation of singlet oxygen, and multiphoton absorption in biological materials may cause physiological damage to cells and other biological objects; and 2) the method relies on complex, potentially expensive optical setups that are difficult to maintain and miniaturize. Electrophoresis/dielectrophoresis based methods are strictly dependent on particle polarizibility and medium conductivity, and utilize electrical forces that may adversely affect cell physiology due to current-induced heating and/or direct electric-field interaction.
"Acoustic-based particle manipulation methods present excellent alternatives. Compared to their optical, electrical, or magnetic counterparts, acoustic-based methods are relatively non-invasive to biological objects and work for most microparticles regardless of their optical, electrical, or magnetic properties. The well developed bulk acoustic wave (BAW) acoustophoresis has demonstrated the separation of cells based on size and density in microfluidic chips without any labeling on the target particles or cells. This BAW method, however, requires a channel material with excellent acoustic reflection properties (such as silicon and glass). The widely used soft polymer materials in microfluidic applications, such as PDMS, usually do not have those properties. Moreover, the transducer to generate BAW is bulky and hinders the system integration and miniaturization."
In addition to the background information obtained for this patent application, VerticalNews journalists also obtained the inventors' summary information for this patent application: "The present invention provides a unique design based on a surface acoustic wave method. Some versions demonstrate a high separation efficiency with separation efficiency of 98% or higher. Cell viability, proliferation, and apoptosis tests were carried out to confirm the excellent biocompatibility of this device.
"An example apparatus for separating particles within a fluid sample comprises a substrate, one or more transducers for generating a surface acoustic wave (SAW) in the substrate, and a channel configured to receive a fluid sample including one or more species of particle. The fluid sample may be a sample fluid flow, and the sample fluid flow may have a focused, separated, or otherwise sorted particle stream after passing through the particle manipulation portion of the channel. The channel direction or flow direction is at an oblique angle to the direction of the SAWs. The SAWs may be standing surface acoustic waves (SSAWs)
"Examples of the present invention provide novel methods and apparatus for high-efficiency separation of micro/nano particles and cells using angled or tilted surface acoustic waves on a single-layer planar microfluidic device fabricated using standard soft-lithography techniques. Systems include a low cost, high efficiency, and portable separation system for many applications such as blood/cell/particle separation, cells/particles medium exchange, and cells/particles enrichment.
"A channel has a particle manipulation portion where the channel is proximate a SAW region of the substrate, for example extending over the SAW region. The SAW region can be defined using a patterned material on the substrate. The channel may be provided by a formed element, such as a molded polymer formed element, adjacent the substrate. The particle manipulation portion of the channel provides particle manipulation within the fluid sample when a surface acoustic wave is generated. The fluid sample may comprise particles suspended in a liquid, such as an aqueous medium.
"In some examples, the substrate is a piezoelectric substrate, and the SAW is generated using a transducer supported by the substrate. A standing surface acoustic wave (SSAW) may be generated using a pair of surface acoustic wave generators (SAW generators), which may each be an interdigitated transducer (IDT). The SAW generators may be spaced apart on the substrate, and the SAW region of the substrate is located where SAWs interact on the surface. In some examples, a pair of SAW generators is used, and the particle manipulation region of the channel is located between the SAW generators, e.g. mechanically coupled to a SAW region of the substrate so that the SAW generates pressure forces within the fluid sample.
"Example apparatus include microfluidic devices, the channel being a microchannel having at least one cross-sectional dimension (such as width or height) less than 10 mm, or less than 1 mm for some versions, for example between 1 micron and 500 microns, and the particles may be microparticles such as cells, biomolecules, polymer beads, blood components such as red and white blood cells, platelets, proteins, and the like.
"An apparatus may be a particle characterization apparatus further including a particle characterization device, the particle characterization device characterizing the manipulated particles. Particle characterization may include counting, sorting, detecting (including selective detection of one or more particle species), or otherwise characterizing particles, and may include diagnosis of a human disorder based on the presence or properties of a biological fluid component. Examples include blood, saliva, urine, and other biological fluid characterization including manipulation of particles within the biological fluid. A particle characterization apparatus may include a radiation source providing a radiation beam incident on the manipulated particles, and/or a sensor receiving radiation scattered or otherwise obtained from the particles. Example particle characterization apparatus include a cytometer (such as a flow cytometer), fluorescence particle detector, fluorescence spectrometer, fluorescence-activated particle sorter, other particle sorter, particle counter, fluorescent spectrometer, biomarker detector, or genetic analyzer. Particles may be cells (e.g. human cells), biomolecules, other bioparticles, or any other type of particle of interest.
"An example method of particle manipulation within a fluid sample including the particles comprises introducing the fluid sample to a channel proximate a substrate, and generating a SAW or SSAW on the substrate at an oblique angle to the channel direction. A SAW is an acoustic wave propagating along the surface of the substrate, and the surface may also be in contact with a fluid sample. The SAWs may interact to form a SSAW. The term acoustic does not limit the frequency of the SAW, which may greater than 1 GHz. Manipulated particles may be particles within a region of enhanced particle concentration within a liquid.
"The SAW induces pressure forces within the fluid so as to focus the particles within the fluid sample. The sample flow may be directed along a flow channel, the flow channel being supported by the substrate in which the SAW is generated. A SAW may be used to obtain three-dimensional manipulation of the particles within the sample flow, the particles being manipulated in directions both parallel and normal to the substrate.
"A novel on-chip micro/nano particle manipulation technique was developed using standing surface acoustic waves (SSAWs). Example methods and apparatus are efficient, simple, fast, dilution-free, and applicable to virtually any type of particle, including both charged and uncharged microparticles. Example methods can be used with flow cytometry, cell sorting/counting, on-chip cell manipulation, tissue engineering, regenerative medicine, non-human animal diagnosis, and many other applications.
"An example apparatus, such as a microfluidic device, receives a sample flow including particles. The apparatus comprises a substrate, a channel (such as a flow channel) into which the sample is introduced, and one or more surface acoustic wave (SAW) generators. A SAW generator may be an interdigitated transducer (IDT, sometimes termed an interdigital transducer) comprising interdigitated comb-shaped electrodes on a piezoelectric substrate. The channel may pass between a pair of IDTs. The IDTs and channel may both be supported by the same piezoelectric substrate. The SAW generators may be operated to produce a SAW or SSAW in a portion of the substrate proximate (possibly immediately adjacent to) the manipulation portion of the flow channel. For example, a flow channel may be supported by the substrate, e.g. formed by a structure comprising a polymer or other material bonded to the substrate.
"The flow channel has a particle manipulation region located on a portion of the substrate in which the SAW exists. For example, the flow channel may pass over a portion of the substrate having standing surface acoustic waves (SSAWs), the particles being manipulated within the flow channel by the effects of the SSAW. The substrate may be a generally planar substrate, for example a ferroelectric and/or piezoelectric substrate. A surface acoustic wave generator may comprise interdigitated electrodes supported by a ferroelectric or piezoelectric substrate. Two or more SAW generators may be used to generate a SSAW in the substrate, e.g. using interference effects between SAWs.
"A method of manipulating particles within a sample, such as focusing, separating, or sorting, which may be a method of three-dimensional particle manipulation, includes producing a standing surface acoustic wave (SSAW), pressure waves within the sample generated as a result of the SSAW producing particle manipulation. The sample may be a sample flow moving through a channel, the channel having a particle manipulation region over a portion of the substrate in which the SSAW exists.
"An apparatus for three-dimensional particle manipulation of particles within a fluid sample comprises a substrate having a substrate surface, a surface acoustic wave generator, operable to generate a surface acoustic wave (SAW, such as a SSAW) within a SAW region of the substrate surface, a channel configured to receive the fluid sample, the channel having a particle manipulation portion proximate the SAW region of the substrate, the particle manipulation portion providing manipulated particles within the fluid sample when the SAW is generated. The substrate surface may form a wall of the channel, and the SAW region of the substrate may form a wall of the particle manipulation portion of the channel.
BRIEF DESCRIPTION OF THE DRAWINGS
"FIG. 1 is a schematic top view of a particle manipulation apparatus in accordance with the present invention;
"FIG. 2 is a cross sectional schematic view showing the interaction of SSAWs with particles in a channel;
"FIGS. 3A-3C illustrate the trajectories taken by two different particle types in the presence of SSAWs disposed at an oblique angle of 15, 30 and 45 degrees, respectively, to the direction of flow;
"FIGS. 4A-4C illustrate the trajectories taken by a particle in the presence of SSAWs having three different input power levels;
"FIG. 5 is a schematic view similar to FIG. 1, with a working region indicated in dot-dash lines;
"FIG. 5A illustrates the trajectories of two particle types in a fluid flow in the working region of FIG. 5, with the SAW generators turned off;
"FIG. 5B illustrates the trajectories of two particle types in a fluid flow in the working region of FIG. 5, with the SAW generators turned on;
"FIG. 5C is a schematic view similar to FIG. 5A, with an outlet region indicated in dot-dash lines;
"FIG. 5D illustrates the trajectories of two particle types in a fluid flow in the outlet region of FIG. 5C, with the SAW generators turned off;
"FIG. 5E illustrates the trajectories of two particle types in a fluid flow in the outlet region of FIG. 5C, with the SAW generators turned on;
"FIG. 6 is a graph presenting experimental data on the separation efficiency of the present invention;
"FIG. 7 is a schematic view similar to FIG. 1, with a working region indicated in dot-dash lines;
"FIG. 7A illustrates the trajectories of two particle types in a fluid flow in the working region of FIG. 7, in the presence of SSAWs;
"FIG. 7B is a schematic view similar to FIG. 7, with an outlet region indicated in dot-dash lines;
"FIG. 7C illustrates the trajectories of two particle types in a fluid flow in the outlet region of FIG. 7B, in the presence of SSAWs;
"FIG. 8 is a schematic view similar to FIG. 1, with a working region indicated in dot-dash lines;
"FIG. 8A illustrates the trajectories of two particle types in a fluid flow in the working region of FIG. 8, in the presence of SSAWs;
"FIG. 8B is a schematic view similar to FIG. 8, with an outlet region indicated in dot-dash lines;
"FIG. 8C illustrates the trajectories of two particle types in a fluid flow in the outlet region of FIG. 8B, in the presence of SSAWs;"
URL and more information on this patent application, see: Ding, Xiaoyun; Huang,
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