Patent Description:
Cell identification and counting play an important role in medical diagnostics and life sciences research. Advancements in cell identification and counting technologies have enabled rapid and automated cell identification and counting.

Conventional methods for cell analysis include delivering through a fluidic channel (e.g., flow cytometry). However, challenges associated with fluidic mechanics have limited the throughput of such methods. <CIT> discloses a microfluidic device including a microfluidic channel that allows fluid including one or more droplets to pass through the microfluidic channel. The device optionally comprises a plurality of traps positioned in the microfluidic channel and arresting the trapped droplet's movement in the channels. Biological cells thus move through a closed fluidic system. <NPL>, discloses a simulated split-ring microstrip microwave sensor comprising a substrate and a ring structure made of copper. The sensor measures the transmission of microwave radiation in the gap region of the ring.

The devices and methods described herein address challenges associated with conventional devices and methods for identifying and counting biological cells.

In accordance with the invention, a device for analyzing biological cells includes a first platter for positioning a first group of biological cells; a first head positioned adjacently to the first platter for providing first electromagnetic radiation to at least a first subset of the first group of biological cells; and a first electrode positioned adjacently to the first platter for detecting the first electromagnetic having interacted with the first subset of the first group of biological cells for determining impedance values for the first subset of the first group of biological cells. The first head is located above the first platter and the first electrode is located under the first platter , or vice versa, with the lateral locations of the first head and the first electrode corresponding to each other.

In accordance with the present invention, a method includes providing, with a first head positioned adjacently to a first platter, first electromagnetic radiation to at least a first subset of a first group of biological cells positioned with the first platter; detecting, with a first electrode positioned adjacently to the first platter, the first electromagnetic radiation having interacted with at least the first subset of the first group of biological cells; and determining, with one or more processors, one or more impedance values for the first subset of the first group of biological cells based on the first electromagnetic radiation detected by the first electrode. The first head is located above the first platter and the first electrode is located under the first platter , or vice versa, with the lateral locations of the first head and the first electrode corresponding to each other.

Thus, the disclosed devices and methods allow determining impedance of biological cells using electromagnetic radiation. The determined impedance can be used for counting and identifying biological cells and in some cases, subcellular components. The disclosed devices and methods may replace, or complement, conventional devices and methods.

For a better understanding of the various described embodiments, reference should be made to the Description of Embodiments below, in conjunction with the following drawings in which like reference numerals refer to corresponding parts throughout the figures.

Reference will be made to embodiments, examples of which are illustrated in the accompanying drawings. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the various described embodiments. However, it will be apparent to one of ordinary skill in the art that the various described embodiments may be practiced without these particular details. In other instances, methods, procedures, components, circuits, and networks that are well-known to those of ordinary skill in the art are not described in detail so as not to unnecessarily obscure aspects of the embodiments.

For example, a first cantilever could be termed a second cantilever, and, similarly, a second cantilever could be termed a first cantilever, without departing from the scope of the various described embodiments. The first cantilever and the second cantilever are both cantilevers, but they are not the same cantilever.

The terminology used in the description of the embodiments herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the scope of claims. As used in the description and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will also be understood that the term "and/or" as used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items.

<FIG> shows a device <NUM> for analyzing biological cells in accordance with some embodiments.

The device <NUM> includes a platter <NUM> for positioning a first group of biological cells <NUM>. For example, the biological cells may be positioned (directly or indirectly) on the platter <NUM>, over the platter <NUM>, or at least partially in the platter <NUM>. In some embodiments, the biological cells <NUM> are positioned on only one (substantially planar) surface of the platter <NUM>. In some embodiments, the biological cells <NUM> are positioned on both (substantially planar) surfaces of the platter <NUM>.

The device also includes a head <NUM> positioned adjacently to the platter <NUM> for providing first electromagnetic radiation to at least a first subset of the first group of biological cells <NUM>. In <FIG>, the head <NUM> is coupled with a head actuator <NUM> for moving the head <NUM> relative to the platter <NUM>. For example, the head actuator <NUM> moves the head <NUM> in a direction that is not perpendicular to a radial direction of the platter <NUM> so that the head <NUM> can move over between an inside track (e.g., located adjacent to a center of the platter <NUM>) and an outside track (e.g., located away from the center of the platter <NUM>) of the platter <NUM>. In some embodiments, the head actuator <NUM> includes an arm <NUM> and a motor <NUM> (e.g., a stepper motor) coupled with the arm <NUM>.

Electromagnetic radiation may have any frequency (e.g., between <NUM> and <NUM> THz). In some implementations, the electromagnetic radiation includes microwave electromagnetic radiation having a frequency between <NUM> to <NUM>. In some implementations, the electromagnetic radiation has a frequency between <NUM> to <NUM>. In some implementations, the electromagnetic radiation has a frequency on the order of KHz to MHz (e.g., between <NUM> to <NUM>).

The device <NUM> further includes an electrode positioned adjacently to the platter <NUM> for detecting the first electromagnetic having interacted with the first subset of the first group of biological cells <NUM> for determining impedance values for the first subset of the first group of biological cells <NUM>. In some embodiments, the device includes an electrode actuator <NUM> for moving the electrode relative to the platter <NUM>. For example, the electrode actuator <NUM> moves the electrode in a direction that is not perpendicular to the radial direction of the platter <NUM> so that the electrode can move under between the inside track and the outside track of the platter <NUM>.

In some embodiments, the electrode is positioned at a location corresponding to a location of the head <NUM> (e.g., the head <NUM> may be located above the platter <NUM> and the electrode may be located under the platter <NUM>, or vice versa, with their lateral locations corresponding to each other). For example, a controller provides electrical signals to both the head actuator <NUM> and the electrode actuator <NUM> so that both the head <NUM> and the electrode are positioned at laterally corresponding locations (e.g., the head <NUM> is located directly above or below the electrode).

Although <FIG> shows that the head <NUM> and the electrode are moved by two separate actuators, namely the head actuator <NUM> and the electrode actuator <NUM>, in some embodiments, a single actuator moves both the head <NUM> and the electrode concurrently.

<FIG> is a cross-sectional view of the device shown in <FIG> in accordance with some embodiments.

In addition to the platter <NUM> and the head <NUM> shown in <FIG>, <FIG> shows an electrode <NUM> for detecting the first electromagnetic having interacted with the first subset of the first group of biological cells <NUM>, and a platter actuator <NUM> (e.g., an assembly including a motor, such as a stepper motor) for rotating the platter <NUM> (e.g., spinning the platter <NUM> about an axis of rotational symmetry for the platter <NUM>). For example, the platter actuator <NUM> includes a rotatable shaft that is coupled with the platter <NUM> (e.g., at least while the head <NUM> provides the first electromagnetic radiation). In <FIG>, the electrode <NUM> is mounted on the electrode actuator <NUM>.

<FIG> also shows that the electrode <NUM> is electrically coupled with an electrical circuit <NUM> for reading the electrical signals (e.g., radio-frequency signals) detected by the electrode <NUM>.

In some embodiments, the head <NUM> includes a coil, as shown in <FIG>, for providing electromagnetic radiation. In some embodiments, the head <NUM> includes an oscillator (e.g., a combination of the coil or an inductor with a capacitor). In some embodiments, the oscillator generates microwave electromagnetic radiation. In some embodiments, the head <NUM> is configured to change a frequency of the generated electromagnetic radiation (e.g., by changing a capacitance of the capacitor coupled with the inductor) so that the impedance can be measured at multiple frequencies of the electromagnetic radiation or scanned over a range of frequencies. Such scanning allows broadband electrical detection of cells, which can differentiate, for example, live and dead cells.

Shown in the inset of <FIG> is another structure of a head, which can provide a localized magnetic field. The head includes electrodes <NUM> and <NUM> and a metallic interlayer <NUM> together with a field generation layer <NUM> and a layer <NUM> with perpendicular anisotropy between the electrode <NUM> and the metallic interlayer <NUM>, and a perpendicularly magnetized reference layer <NUM> located between the electrode <NUM> and the metallic interlayer <NUM>. In some implementations, once an electrical field is applied to the electrodes <NUM> and <NUM>, an oscillating stack (e.g., a combination of the layers <NUM> and <NUM>) produces precession of magnetic dipoles in the layer <NUM>. This precessing dipole is a function of the injected current density and it creates an alternating current field on a single biological cell <NUM>. The resulting current and/or voltage can be used to measure the real and imaginary components of the cell impedance.

Other head structures may be used for providing electromagnetic radiation.

<FIG> shows a device <NUM> for analyzing biological cells in accordance with some embodiments. The device <NUM> is similar to the device <NUM> shown in <FIG>, except that the device <NUM> includes a second head <NUM> (which may be coupled to a second head actuator <NUM>) and a second electrode (which may be coupled to a second electrode actuator <NUM>). The second head <NUM> is distinct from the first head <NUM> and is positioned at a location distinct from a location of the first head <NUM>. Yet, the second head <NUM> is positioned adjacently to the platter <NUM> for providing second electromagnetic radiation (e.g., to biological cells positioned with the platter <NUM>). Similarly, the second electrode is positioned at a location distinct from a location of the first electrode. The second electrode is positioned adjacently to the platter <NUM> for detecting the second electromagnetic radiation having interacted with at least a second subset of the first group of biological cells for determining impedance values for the second subset of the first group of biological cells.

Although <FIG> shows two heads <NUM> and <NUM>, in some embodiments, the device <NUM> may include three or more heads. Similarly, in some embodiments, the device <NUM> may include three or more electrodes for detecting electromagnetic radiations having interacted with one or more subsets of the first group of biological cells.

In some embodiments, the head <NUM> and the second head <NUM> are configured to provide electromagnetic radiations having a corresponding frequency. When the first subset and the second subset are identical or include common biological cells, this allows second determination of impedance values (e.g., for the same biological cells), which may be used to improve the reliability and accuracy of the determined impedance values. Alternatively, when the first subset and the second subset are mutually exclusive, the first head <NUM> and the second head <NUM> may be positioned for determining impedance values of different biological cells. For example, when the cells are arranged like tracks of a hard-disk drive, the first head <NUM> is positioned for odd-numbered tracks while the second head <NUM> is positioned for even-numbered tracks. This increases the scan speed so that impedance values of more biological cells for electromagnetic radiation of a particular frequency can be determined for a given amount of time.

In some embodiments, the first electromagnetic radiation has a first frequency and the second electromagnetic radiation has a second frequency that is distinct from the first frequency. For example, the head <NUM> and the second head <NUM> may provide electromagnetic radiation of different frequencies so that the head <NUM> (and the associated electrode) are used for determining impedance values of biological cells at a first frequency and the second head <NUM> (and the associated second electrode) are used for determining impedance values of biological cells at a second frequency. The head <NUM> and the second head <NUM>, for example, may be configured to provide electromagnetic radiation of different frequencies by using capacitors having different capacitance values and/or inductors having different inductance values in the oscillator circuits of the heads <NUM> and <NUM>.

<FIG> is an example impedance graph in accordance with some embodiments. The graph shows an impedance function <NUM> with impedance values of a particular biological cell for a range of electromagnetic radiation frequencies. Instead using a single impedance value, using an impedance function allows better identification and counting of cells (e.g., the precision and accuracy are improved over using a single impedance value).

<FIG> shows a device <NUM> for analyzing biological cells in accordance with some embodiments. The device <NUM> is similar to the device shown in <FIG>, except that the device <NUM> includes multiple platters, such as a second platter <NUM> and a third platter <NUM>. Although <FIG> shows that the device <NUM> has three platters, in some embodiments, the device <NUM> may have fewer platters (e.g., two platters) or more platters (e.g., four or more platters).

<FIG> also shows that each platter is coupled with at least one head and at least one electrode. For example, the second platter <NUM> is coupled with a head <NUM> (coupled with a head actuator <NUM>) and a corresponding electrode (coupled with an electrode actuator <NUM>), and the third platter <NUM> is coupled with a head <NUM> (coupled with a head actuator <NUM>) and a corresponding electrode (coupled with an electrode actuator <NUM>). In some embodiments, at least one platter of the multiple platters is coupled with two or more heads and two or more electrodes, in a manner analogous to that shown in <FIG>. Multiple platters provide an increased capacity so that additional biological cells may be analyzed by the device. In addition, because biological cells are arranged on multiple platters, additional heads and electrodes may be used to further increase the speed of analyzing biological cells. Furthermore, the use of multiple platters allows each platter to be rotated at different speeds (e.g., depending on the required scanning time and/or accuracy).

In some embodiments, at least one platter (e.g., platter <NUM>) of the multiple platters is used as a reference platter. The reference platter may have biological cells (e.g., biological cells different from the biological cells on other platters, such as control biological cells) thereon or may not have biological cells (e.g., the reference platter may be with or without biological cells). One or more electrodes are positioned adjacently to the reference platter for detecting electromagnetic radiation. The electromagnetic radiation detected using the reference platter may be used to process electrical signals from electrodes coupled with other platters (e.g., for canceling noises, etc.).

<FIG> is a block diagram illustrating electrical components for analyzing biological cells in accordance with some embodiments.

In some embodiments, the device for analyzing biological cells includes one or more processors <NUM> and memory <NUM>. In some embodiments, the memory <NUM> includes instructions for execution by the one or more processors <NUM>. In some embodiments, the stored instructions include instructions for receiving electrical signals indicative of one or more impedance values for the first subset of the first group of biological cells (e.g., from the electrodes) and instructions for determining the one or more impedance values for the first subset of the first group of biological cells from the received electrical signals. In some embodiments, the stored instructions also include instructions for storing the one or more impedance values for the first subset of the first group of biological cells (e.g., within the memory <NUM> or another storage device).

In some embodiments, the device also includes an electrical interface <NUM> coupled with the one or more processors <NUM> and the memory <NUM>.

In some embodiments, the device further includes an actuator driver circuit <NUM>, which is coupled to one or more actuators, such as the head actuator <NUM>, the electrode actuator <NUM>, the second head actuator <NUM>, and the second electrode actuator <NUM>. The actuator driver circuit <NUM> sends electrical signals to the one or more actuators <NUM>, <NUM>, <NUM>, and <NUM> to initiate movement of the one or more actuators.

In some embodiments, the device includes a head driver circuit <NUM>, which is coupled to one or more heads, such as the head <NUM> and the second head <NUM>. The head driver circuit <NUM> sends electrical signals to the one or more heads <NUM> and <NUM> to generate electromagnetic radiation using the one or more heads.

In some embodiments, the device includes a readout circuit <NUM> (e.g., electrical circuit <NUM>) coupled with one or more electrodes, such as the electrode <NUM> and an electrode <NUM> (which may be coupled to the second electrode actuator <NUM>). The readout circuit <NUM> receives electrical signals from the one or more electrodes <NUM> and <NUM> and relays the electrical signals to the one or more processors (with or without processing, such as filtering, etc.).

<FIG> is a flow diagram illustrating a method <NUM> of analyzing biological cells in accordance with some embodiments.

The method <NUM> includes (<NUM>) providing, with a first head positioned adjacently to a first platter, first electromagnetic radiation to at least a first subset of a first group of biological cells positioned with the first platter (e.g., the head <NUM> positioned adjacent to the platter <NUM> provides the first electromagnetic radiation to at least a subset of biological cells <NUM> on the platter <NUM>).

In some embodiments, the method <NUM> includes (<NUM>) rotating the first platter while the first electromagnetic radiation is being provided so that a plurality of biological cells of the first group receive the first electromagnetic radiation sequentially (e.g., using the platter actuator <NUM>).

In some embodiments, the method <NUM> includes (<NUM>) changing a frequency of the first electromagnetic radiation while the first platter rotates. For example, the frequency of the first electromagnetic radiation is gradually changed to cover a certain frequency range so that impedance values of the biological cell for the frequency range can be obtained. In some cases, the impedance values of the biological cell over the frequency range (which may be plotted as a graph as shown in <FIG>) may be used to identify the biological cell.

The method <NUM> includes (<NUM>) detecting, with a first electrode positioned adjacently to the first platter, the first electromagnetic radiation having interacted with at least the first subset of the first group of biological cells. For example, the electrical signals detected by the electrode <NUM> is read, or quantized, by the electrical circuit <NUM>.

The method <NUM> includes (<NUM>) determining, with one or more processors, one or more impedance values for the first subset of the first group of biological cells based on the first electromagnetic radiation detected by the first electrode. For example, the one or more processors <NUM> process the electrical signals from the electrical circuit <NUM> (e.g., filtering, averaging, scaling, etc.) to determine one or more impedance values of one or more biological cells. In some embodiments, determining the one or more impedance values includes determining an attenuation and a phase delay (e.g., for determining real and imaginary components of the impedance value).

In some embodiments, the method includes (<NUM>) providing, with a second head (e.g., the second head <NUM>) positioned adjacently to the first platter, second electromagnetic radiation concurrently with providing the first electromagnetic radiation with the first head; detecting, with a second electrode positioned adjacently to the first platter, the second electromagnetic radiation having interacted with at least a second subset of the first group of biological cells; and determining, with the one or more processors, one or more impedance values for the second subset of the first group of biological cells based on the first electromagnetic radiation detected by the second electrode.

In some embodiments, the first electromagnetic radiation has (<NUM>) a first frequency and the second electromagnetic radiation has a second frequency that is distinct from the first frequency.

In some embodiments, the method <NUM> includes (<NUM>) providing, with a third head (e.g., the third head <NUM>) positioned adjacent to a second platter, third electromagnetic radiation concurrently with providing the first electromagnetic radiation with the first head; detecting, with a third electrode positioned adjacently to the second platter, the third electromagnetic radiation having interacted with at least a subset of a second group of biological cells positioned with the second platter; and determining, with the one or more processors, one or more impedance values for the subset of the second group of biological cells based on the third electromagnetic radiation detected by the third electrode.

In some embodiments, the method <NUM> includes rotating the second platter while the third electromagnetic radiation is being provided so that a plurality of biological cells of the second group receive the third electromagnetic radiation sequentially. In some embodiments, the first platter and the second platter are rotated concurrently.

Claim 1:
A device for analyzing biological cells, the device comprising:
a first platter (<NUM>) for positioning a first group of biological cells (<NUM>);
a first head (<NUM>) positioned adjacently to the first platter (<NUM>) for providing first electromagnetic radiation to at least a first subset of the first group of biological cells (<NUM>); and
a first electrode (<NUM>) positioned adjacently to the first platter (<NUM>) for detecting the first electromagnetic radiation having interacted with the first subset of the first group of biological cells (<NUM>) for determining impedance values for the first subset of the first group of biological cells (<NUM>),
characterized in that
the first head (<NUM>) is located above the first platter (<NUM>) and the first electrode (<NUM>) is located under the first platter (<NUM>), or vice versa, with the lateral locations of the first head (<NUM>) and the first electrode (<NUM>) corresponding to each other.