Linear fluid cell capture device for single cell detection

Abstract

A sensing structure (101) is provided and comprises: a tubular element (110) through which a fluid can flow along a single path; an array of sensors (1201-5) disposed along the length of the tubular element, whereby fluid can flow through each of the sensors; and a sensing circuit electrically connected to each of the sensors and configured to measure a reactance of each of the sensors and determine whether any reactance is indicative of the presence of biological cells in the fluid flowing through the corresponding sensor.

Description

BACKGROUND

[0001] The present invention relates generally to detection systems. More particularly, the present invention relates to linear fluid cell capture devices for single cell detection.

[0002] Single cells represent the basic biological unit. Unfortunately, biological knowledge is often obtained by studying large cell populations due to the availability of simple, fast-to-use, inexpensive instrumentation and / or ease of sample preparation. However, there remain fundamental and applied problems that can only be solved at the single cell level, such as problems related to transcriptional control of stem cell differentiation, intrinsic noise in gene expression, and disease origination.

[0003] In addition, identifying individual bacterial cells or viral particles is of great importance for identifying food or product contamination and individual health monitoring, respectively. Identifying individual bacterial cells can help identify contamination of pathogenic bacteria in food or products. Identifying viral particles can help determine whether a sick individual is infected with Covid or common flu virus, preferably at home without visiting a diagnostic laboratory or a doctor’s office. SUMMARY

[0004] Embodiments of the present invention relate to a sensing structure. A non-limiting example of a sensing structure is provided that includes a tubular element through which a fluid can flow along a single path, an array of sensors arranged along a length of the tubular element through which the fluid can flow, and a sensing circuit electrically connected with each of the sensors, the sensing circuit configured to measure a reactance of each of the sensors and determine whether any of the reactances indicates a presence of a biological cell in the fluid flowing through the corresponding sensor.

[0005] Embodiments of the present invention relate to a sensing structure. A non-limiting example of a sensing structure includes a bottom wafer, a top wafer, an insulator layer interposed between the bottom wafer and the top wafer and formed to define a channel through which a fluid can flow along a single path, a sensor disposed along a length of the channel, whereby the fluid can flow through each of the sensors, and a sensing circuit electrically connected with each of the sensors, the sensing circuit configured to measure at least one of a capacitance and an inductance of each of the sensors and determine whether any of the at least one of the capacitance and the inductance indicates a presence of a biological cell in the fluid flowing through the corresponding sensor.

[0006] Embodiments of the invention relate to a method of operating a sensing structure for sensing biological cells in a fluid. Non-limiting examples of the method include arranging sensors into an array along a single path, obtaining a baseline reactance for each of the sensors, flowing the fluid along the single path through the sensors in the array, obtaining a test reactance for each of the sensors during the flow of the fluid, and determining whether a difference exists between the baseline reactance and the test reactance for each of the sensors and that difference is indicative of the presence of a biological cell.

[0007] Additional technical features and benefits are realized through the techniques of the present invention. Embodiments and aspects of the invention are described in detail herein and are considered a part of the claimed subject matter. For a better understanding, refer to the specific embodiments and the accompanying drawings. BRIEF DESCRIPTION OF DRAWINGS

[0008] The details of the application described herein are particularly pointed out and distinctly claimed in the claims section appended hereto. The foregoing and other features and advantages of the embodiments of the present application are apparent from the following detailed description taken in conjunction with the accompanying drawings in which:

[0009] Figure 1A is a side view of a sensing structure in accordance with one or more embodiments of the present invention and a graphical illustration of readings from the sensing circuit of the sensing structure;

[0010] Figure 1B is a side view of a sensing structure in accordance with one or more embodiments of the present invention and a graphical illustration of readings from the sensing circuit of the sensing structure; Figure 1A

[0011] Figure 2 is a schematic top view illustrating a sensing structure in accordance with one or more embodiments of the present invention;

[0012] Figure 3 is a side view of a sensing structure in accordance with one or more embodiments of the present invention and a graphical illustration of readings from the sensing circuit of the sensing structure; Figure 2 Figure 2 is a side view of a sensing structure in accordance with one or more embodiments of the present invention and a graphical illustration of readings from the sensing circuit of the sensing structure;

[0013] Figure 4 Figure 2 is a side view of a sensing structure in accordance with one or more embodiments of the present invention and a graphical illustration of readings from the sensing circuit of the sensing structure; Figure 2

[0014] Figure 5 is a flowchart illustrating a method of operating a sensing structure for sensing biological cells in a fluid in accordance with one or more embodiments of the present invention;

[0015] Figure 6 is a flowchart illustrating a method of constructing a sensing structure in accordance with one or more embodiments of the present invention; and ​​​​

[0016] Figure 7A and Figure 7B is a graphical flowchart illustrating a method of fabricating a sensing structure in accordance with one or more embodiments of the present application. Figures 2 to 4

[0017] The figures depicted herein are illustrative. Numerous variations are possible without departing from the spirit of the present application. For instance, the acts can be performed in a different order from that described, or additional, deleted, or modified acts can be added to the described acts. Further, the term "coupled" and variations thereof describes having a communications path between two elements and does not imply a direct connection between the elements, with no intermediary elements / connections between them. All such variations are considered to be part of the specification.

[0018] In the drawings of the described embodiments and in the following detailed description, various elements illustrated in the figures have two or three digit reference labels. The left-most digit(s) of each reference label corresponds to the figure in which its element is first illustrated. The remaining digits correspond to the particular element. DETAILED DESCRIPTION

[0019] For the sake of brevity, conventional techniques related to semiconductor devices and integrated circuit (IC) fabrication can or can not be described in detail herein. Moreover, the various tasks and process steps described herein can be incorporated into more comprehensive programs or processes having additional steps or functionality, some of which are not described herein. In particular, various steps in the manufacture of semiconductor devices and semiconductor-based ICs are well known and so, in the interest of brevity, many conventional steps are only mentioned briefly herein or are omitted entirely without providing the well-known processing details.

[0020] Turning now to an overview of the technology more specifically related to aspects of the present application, existing methods for measuring transcript levels in single cells include quantitative reverse transcription polymerase chain reaction (RT-qPCR), single molecule counting using digital PCR, hybridization probes, and next generation sequencing. Of these, single cell RT-qPCR offers a combination of sensitivity, specificity, and dynamic range, but the main drawbacks are low throughput, high reagent cost, and difficulty in accurately measuring low abundance transcripts.

[0021] Turning now to an overview of aspects of the present application, one or more embodiments of the present application address the aforementioned drawbacks of the prior art by providing several (N) linearly connected single cell traps, thereby enabling higher throughput, which is determined by the assay flow rate and sampling speed of the detector. Due to the separate current or voltage stimulation electrodes for each cell having a separate isolated embedded detection / measuring probe within the main path of the stimulation electrode, the measurement accuracy is increased. Additionally, wafer-to-wafer parallel fabrication manufacturing methods result in significantly lower cost. ​

[0022] The above aspects of the present invention address the shortcomings of the prior art by providing a sensing structure comprising: a tubular element through which fluid can flow along a single path; an array of sensors arranged along the length of the tubular element, through which fluid can flow; and a sensing circuit electrically connected to each of the sensors and configured to measure the reactance of each of the sensors and determine whether any reactance indicates the presence of biological cells in the fluid flowing through the corresponding sensor.

[0023] We now turn to a more detailed description of various aspects of the invention. Figure 1A A sensing structure 101 is depicted, comprising: a tubular element 110 through which fluid can flow along a single path 111; and an array of sensors 1201 to 1205, which is designated as 120. 1-5 Sensors 1201 to 1205 are arranged along the length L of the tubular element 110, so that when fluid flows through the tubular element 110 and the sensing circuit 130, fluid can flow through sensor 120. 1-5 Each of the sensors in the sensing circuit 130 and each of the sensors 120. 1-5 Electrically connected and configured to measure sensor 120 1-5 The reactance of each of them is measured and it is determined whether there is any reactance indicating flow through the corresponding sensor 120. 1-5 Biological cells exist in the fluid.

[0024] Sensor 120 1-5 Each of them includes opposing electrodes 121, 122 spaced evenly and regularly along the length L on opposite sides of the tubular element 110. Although in Figure 1A Five sets of sensors 120 are shown. 1-5 However, the sensing structure 101 includes sensor 120 1-5 At least three or more sensors in the group are required to ensure a statistically significant number of detection and identification events occur in a given operation. It should be understood that, in addition to sensor 120... 1-5 An additional number of sensors can be set along length L.

[0025] The sensing circuit 130 includes a processing unit, a memory unit, and a networking or input / output (I / O) unit. The processing unit communicates with the sensor 120 through the networking or input / output (I / O) unit. 1-5The group communicates with external devices. The memory unit has executable instructions stored thereon, which can be read and executed by the processing unit. When the executable instructions are read and executed by the processing unit, they cause the processing unit and sensing circuit 130 to operate substantially as described herein. Specifically, sensing circuit 130 is configured to measure sensor 120. 1-5 At least one of the capacitors and inductors on the array and / or measuring sensors 120 1-5 Each of the capacitors and inductors is at least one of the following.

[0026] The sensing circuit is controllable to obtain the dielectric constant of the fluid within the operating frequency range, both when the fluid contains no biological cells and when the fluid contains biological cells. Furthermore, when the fluid contains only one type of biological cell, the sensor 120 can be calibrated by obtaining the dielectric constant of the fluid within the operating frequency range. 1-5 The array and sensing circuit 130.

[0027] In other words, during the operation of the sensing structure 101, the sensor 120 is obtained by measuring the reactance in the absence of fluid in the tubular member 110. 1-5 The baseline reactance is then determined. Subsequently, the dielectric constant of the fluid can be obtained by measuring the reactance of the fluid flowing through the tubular member 110 under conditions where the fluid is known to contain no biological cells. In this case, the sensing circuit 130 obtains the dielectric constant from the difference between the reactance of the fluid without biological cells and the reactance of the fluid without biological cells. At this point, once the dielectric constant of the fluid is known, the fluid flows through the tubular member 110 under conditions where biological cells may be present. Figure 1A As shown in the graphic elements, the sensing circuit 130 can identify the sensor 120 based on changes in reactance. 1-5 The presence of biological cells at any of these locations.

[0028] Reference Figure 1B The sensing circuit can be used to generate readings that identify the type of biological cells detected by sensing structure 101 as follows: The tubular element 110 is filled with a fluid / buffered medium that does not contain biological cells (i.e., bacteria or viruses) for background measurement. Capacitance or reactance measurements are then performed within a certain frequency range (preferably 0.1 to 100 MHz) to extract the dielectric constant of the background medium. A fluid containing biological cells (i.e., bacteria or viruses or other biological material) is then passed through the tubular element 110, and the same type of frequency scan is repeated to obtain a new dielectric constant within the frequency range. Then, Figure 1BThe different peaks and peak half-widths in the dielectric dispersion curve will show the peaks and peak half-widths corresponding to different types of biological cells. To calibrate the sensing structure 101 to achieve this, dielectric dispersion measurements will be performed using only one type of biological cell at a time. For each iteration, the process will be repeated with different types of biological cells. This data will be used to train a neural network model to identify different types of biological cells.

[0029] refer to Figures 2 to 4 A top view of a sensing structure 201 is provided, which includes a bottom wafer 210, a top wafer 220, an insulating layer 230, and a sensor assembly 240. 1-5 And the IC integrated sensing circuit 250 shown here. An insulating layer 230 is situated between a bottom wafer 210 and a top wafer 220 and is formed to define a channel 235 through which fluid can flow along a single path 236. Sensor 240 1-5 Set along the length L of channel 235, so that when fluid flows through channel 235, fluid can flow through each of the sensors 240. 1-5 The sensing circuit 250 is configured similarly to the sensing circuit 130 in FIG1, and is connected to the sensor 240. 1-5 Each electrical connection in the circuit. The sensing circuit 250 can be provided as follows: Figure 2 The integrated IC shown or the external features shown in Figure 1 are configured as a measurement sensor 240. 1-5 At least one of the capacitance and inductance of each, and determine whether either of the at least one capacitance and inductance indicates flow through the corresponding sensor 240. 1-5 Biological cells exist in the fluid.

[0030] like Figure 2 As shown in the magnified image, sensor 240 1-5 It can include reference sensors (C) that are intersected with each other along length L. R ) and sample sensor (C S In any case, sensor 240 1-5 Each of these may include a pair of ground-signal-ground (GSG) electrodes 241 on opposite sides of channel 235.

[0031] The sensing circuit 250 may include multiple (e.g., four) probes 251. Each probe 251 includes a pad 252 exposed to the outside of the sensing structure 201 and a connection to the reference sensor C. R and sample sensor C SThe probe tip 253 corresponds to the sensor electrical contact in the reference sensor C, and the metallization layer 254 extends through the insulating layer 230 between the corresponding pad 252 and each corresponding probe tip 253. According to an embodiment, the probe tip 253 of each probe 251 can be configured to contact the reference sensor C. R and sample sensor C S The adjacent sensors are electrically connected, and the probes 251 can have overlapping probe tips 253.

[0032] like Figure 3 As shown, the probe tips 253 of two probes 251 can be arranged along the same sidewall of the channel 235, while the probe tips of two other probes 251 can be arranged opposite each other on the top and bottom walls of the channel 235. As an example, some probe tips 253 (i.e., stimulation probes) can be arranged on the top and bottom walls of the channel 235, and other probe tips 253 (i.e., measurement sensing probes) can be arranged along the same sidewall of the channel 235, or as... Figure 2 China Figure 2 The right and left sides of the magnified image are labeled "Probe 251". In each case, as... Figure 2 As shown in the magnified image, probe tips 253 can be shifted relative to each other along length L in an alternating ground-probe-ground arrangement to avoid generating noise or otherwise affecting capacitance / inductance readings. In addition to contributing to noise immunity, the measurement sensing probe and contact are positioned on the side of channel 235 opposite to the stimulation probe.

[0033] Figure 4 yes Figure 2 The cross-section marked CC in the non-magnified image shows that channel 235 can have at least two inlets 237 and 238 through which fluid can be directed into channel 235. This allows sensing structure 201 to be initialized and calibrated (similar to that described above), and provides an outlet for trapped air or gas that would otherwise obstruct the desired microfluidic flow. That is, inlet 237 can be used to direct fluid that is known to lack biological cells into channel 235, while inlet 238 can be used to direct fluid that may contain biological cells into channel 235.

[0034] Reference Figure 5 This provides sensing structures for sensing biological cells in fluids (such as sensing structure 101 in Figure 1 and...). Figure 2Method 500 of sensing structure 201. Method 500 includes arranging sensors in an array along a single path (block 501), calibrating the sensors within an operating frequency range (block 502), obtaining a baseline reactance of each of the sensors (block 503), allowing fluid to flow along the single path through the sensors in the array (block 504), obtaining a test reactance of each of the sensors during the fluid flow (block 505), and determining whether a difference exists between the baseline reactance and the test reactance of each of the sensors and whether such difference indicates the presence of biological cells (block 506). Obtaining the baseline reactance and the test reactance of blocks 503 and 505 may each include obtaining the capacitance of each of the sensors, or alternatively, obtaining the baseline reactance and the test reactance of blocks 503 and 505 may each include obtaining the inductance of each of the sensors. Obtaining the baseline reactance of block 503 may include obtaining a first reactance of each of the sensors under empty conditions (block 5031), and obtaining a second reactance of each of the sensors during the flow of fluid without any biological cells (block 5032). The following will be a reference Figure 6 As described, obtaining the test reactance of each of the sensors in box 505 may include continuing the acquisition of box 505 in cases where one or more of the following conditions are met: no statistically significant number of biological cells are detected, data analysis does not detect a sufficient number of detection and recognition events, and neural network training is incomplete. According to one or more embodiments of the invention, method 500 may further include training a neural network model to identify different types of biological cells (box 507).

[0035] Continue to refer to Figure 5 And refer to other sources Figure 6 Now we will describe it in more detail. Figure 5 Method 500. For example... Figure 6 As shown, microfluidic parameters are set at box 601. Then, the relative electrode pairs (Zi) in the reference and sample sensing pair array are measured over a short period (10 to several milliseconds) and within a certain frequency range (preferably 0.1 to 100 MHz). air / C air The capacitance or reactance between the electrodes is used to obtain the first dielectric constant (box 602), and the microfluidic chamber is filled with a buffer fluid that does not contain bacteria, viruses, or animal cells, and the same electrode pair is repeatedly measured in the same frequency range (Z). liq / C liq The capacitance or reactance between the electrodes is used to obtain a second dielectric constant reflecting the dielectric constant of the buffer current (box 603). Next, the buffer current is filled with a buffer current containing bacteria / viruses / animal cells, and the same electrode pair (Z) for the reference and sample sensing pairs is repeated. liq / C liqThe capacitance or reactance between the cells is measured to obtain the dielectric constant of the bacterial / viral / animal cell (box 604).

[0036] At this point, it is determined whether a sufficient number of sensors have detected the passage or presence of biological cells (box 605). If not, control returns to box 601, where the sampling frequency is proportionally reduced and / or the dwell time is increased. If yes, control continues measurement at the same sampling frequency (box 606) and determines whether a statistically significant number of biological cells have been detected (box 607). If no, control returns to box 606. If yes, control continues to run offline data analysis for counting the detected biological cells or for training a model for counting (box 608).

[0037] Next, determine whether the data analysis indicates that sufficient cell detection and identification events have occurred (box 609). If not, control returns to box 606. If yes, control continues to determine whether the training and / or refinement of the neural network model used for online cell counting and type identification has been completed (box 610). If no, control returns to box 606. If yes, control proceeds to end the cell detection and identification loop (box 611).

[0038] Reference Figure 7A and Figure 7B It provides manufacturing at least Figures 2 to 4 The method of sensing structure 201. For example... Figure 7A As shown, the method includes operations 1 to 4, wherein a dielectric material layer is deposited and etched on a wafer; operations 5 to 23, wherein a metallization layer for pads, probe tips, and a plurality of probes is formed in the dielectric material layer; and operation 24, wherein a channel is formed, with each probe tip communicating with the channel. Figure 7B As shown, the method also includes forming a top wafer with additional probes disposed above the channel.

[0039] Various embodiments of the invention are described herein with reference to the accompanying drawings. Alternative embodiments may be devised without departing from the scope of the invention. Although various connections and positional relationships (e.g., above, below, adjacent, etc.) between elements are illustrated in the following description and drawings, those skilled in the art will recognize that many of the positional relationships described herein are orientation-independent, provided that the described functionality is maintained even when the orientation changes. Unless otherwise stated, these connections and / or positional relationships may be direct or indirect, and the invention is not intended to be limited in this respect. Thus, coupling of entities may refer to direct or indirect coupling, and positional relationships between entities may be direct or indirect positional relationships. As an example of an indirect positional relationship, references in this specification to the formation of layer "A" on layer "B" include cases where one or more intermediate layers (e.g., layer "C") are located between layer "A" and layer "B," provided that the relevant characteristics and functions of layers "A" and "B" are substantially not altered by the intermediate layers.

[0040] The following definitions and abbreviations are used to interpret the claims and specification. As used herein, the terms “comprising,” “including,” “containing,” “comprising,” “having,” “having,” “containing,” or any other variation thereof are intended to cover non-exclusive inclusion. For example, a composition, mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to those elements, but may include other elements not expressly listed or inherent to such compositions, mixtures, processes, methods, articles, or apparatus.

[0041] Additionally, the term "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any embodiment or design described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments or designs. The terms "at least one" and "one or more" should be understood to include any integer greater than or equal to one, i.e., one, two, three, four, etc. The term "multiple" is understood to include any integer greater than or equal to two, i.e., two, three, four, five, etc. The term "connection" can include both indirect "connection" and direct "connection."

[0042] References to "an embodiment," "embodiment," "example embodiment," etc., in the specification indicate that the described embodiment may include a particular feature, structure, or characteristic; however, each embodiment may or may not include a particular feature, structure, or characteristic. Furthermore, such phrases do not necessarily refer to the same embodiment. Additionally, when a particular feature, structure, or characteristic is described in connection with an embodiment, it is believed that implementing such a feature, structure, or characteristic in conjunction with other embodiments, whether explicitly described or not, is within the knowledge of those skilled in the art.

[0043] For the purposes described below, the terms “upper,” “lower,” “right,” “left,” “vertical,” “horizontal,” “top,” “bottom,” and their derivatives shall apply to the described structures and methods, as oriented as shown in the accompanying drawings. The terms “overlapping,” “on top of,” “positioned on,” or “positioned on top of” mean that a first element (such as a first structure) is present on a second element (such as a second structure), wherein an intermediate element, such as an interface structure, may be present between the first and second elements. The term “direct contact” means that the first element (such as a first structure) and the second element (such as a second structure) are connected at the interface of the two elements without any intermediate conductive, insulating, or semiconductor layer.

[0044] For ease of description, spatial relative terms such as “below,” “under,” “lower,” “above,” “upper,” etc., are used herein to describe the relationship between one element or feature and another, as shown in the figures. It should be understood that, in addition to the orientation shown in the figures, spatial relative terms are also intended to cover different orientations of the device in use or operation. For example, if the device in the figures is flipped, an element described as “below” or “under” other elements or features would be oriented “above” other elements or features. Thus, the term “below” can encompass both above and below orientations. The device may be oriented in other ways (rotated 90 degrees or in other orientations), and the spatial relative descriptors used herein shall be interpreted accordingly.

[0045] The phrase “selective towards…”, such as “the first element is selective towards the second element”, means that the first element can be etched and the second element can act as an etch stop layer.

[0046] The terms “approximately,” “substantially,” “approximately,” and their variations are intended to include the degree of error associated with a measurement based on a specific quantity of equipment available at the time of application submission. For example, “approximately” could include a range of ±8%, 5%, or 2% of a given value.

[0047] The term "conformal" (e.g., conformal layer) means that the thickness of the layer is substantially the same on all surfaces, or the thickness variation is less than 15% of the nominal thickness of the layer.

[0048] The terms "epitaxygrowth and / or deposition" and "epitaxygrowth formation and / or growth" refer to the growth of a semiconductor material (crystal material) on a deposition surface of another semiconductor material (crystal material), wherein the grown semiconductor material (crystal capping layer) has substantially the same crystal properties as the semiconductor material (seed material) deposited on the deposition surface. During epitaxial deposition, the chemical reactants supplied by the source gas can be controlled, and system parameters can be set such that the deposited atoms reach the deposition surface of the semiconductor substrate with sufficient energy to move on the surface, causing the deposited atoms themselves to orient themselves toward the crystal arrangement of atoms on the deposition surface. The epitaxially grown semiconductor material can have substantially the same crystal properties as the deposition surface on which the epitaxial growth material is formed. For example, an epitaxially grown semiconductor material deposited on a {100} oriented crystal surface can exhibit a {100} orientation. In some embodiments of the invention, the epitaxial growth and / or deposition process can be selectively formed on a semiconductor surface, and material cannot be deposited on exposed surfaces (e.g., silicon dioxide or silicon nitride surfaces).

[0049] As previously mentioned, for the sake of brevity, conventional techniques associated with the manufacture of semiconductor devices and integrated circuits (ICs) may or may not be described in detail herein. However, as background, a more general description of semiconductor device manufacturing processes that can be used to implement one or more embodiments of the present invention will now be provided. Although specific manufacturing operations used to implement one or more embodiments of the present invention may be individually known, the combination of the operations and / or resulting structures described in the present invention is unique. Thus, the unique combination of operations described in conjunction with the manufacture of semiconductor devices according to the present invention utilizes a variety of individually known physical and chemical processes performed on a semiconductor (e.g., silicon) substrate, some of which are described in the following paragraphs.

[0050] Generally, the various processes used to form microchips that will be packaged into ICs fall into four main categories: film deposition, removal / etching, semiconductor doping, and patterning / photolithography. Deposition is any process that grows, coats, or otherwise transfers material onto a wafer. Available techniques include physical vapor deposition (PVD), chemical vapor deposition (CVD), electrochemical deposition (ECD), molecular beam epitaxy (MBE), and more recently, atomic layer deposition (ALD). Removal / etching is any process that removes material from a wafer. Examples include etching processes (wet or dry) and chemical mechanical planarization (CMP). Semiconductor doping alters electrical properties by doping, for example, transistor sources and drains (typically by diffusion and / or by ion implantation). These doping processes are followed by furnace annealing or rapid thermal annealing (RTA). Annealing is used to activate the implanted dopant. Films of both conductors (e.g., polysilicon, aluminum, copper, etc.) and insulators (e.g., various forms of silicon dioxide, silicon nitride, etc.) are used to connect and isolate transistors and their components. Selective doping of individual regions on a semiconductor substrate allows the substrate's conductivity to change with the application of voltage. By creating structures of these various components, millions of transistors can be built and wired together to form the complex circuits of modern microelectronic devices. Semiconductor lithography is the process of forming a three-dimensional relief image or pattern on a semiconductor substrate so that the pattern can be subsequently transferred onto the substrate. In semiconductor lithography, the pattern is formed from a photosensitive polymer called a photoresist. To build the complex structure of the transistors and the many wires connecting the millions of transistors, the photolithography and etching pattern transfer steps are repeated multiple times. Each pattern printed on the wafer is aligned with the previously formed pattern, and conductors, insulators, and selectively doped regions are slowly built up to form the final device.

[0051] The flowcharts and block diagrams in the accompanying drawings illustrate possible implementations of methods for manufacturing and / or operating according to various embodiments of the present invention. Various functions / operations of the method are represented by blocks in the flowcharts. In some alternative implementations, the functions mentioned in the blocks may not occur in the order shown in the figures. For example, two blocks shown consecutively may actually be performed substantially simultaneously, or these blocks may sometimes be performed in reverse order, depending on the functions involved.

[0052] Various embodiments of the present invention have been described above. These descriptions are exemplary and not exhaustive, nor are they limited to the described embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principles of the embodiments, their practical application, or technical improvements to technologies found in the market, or to enable those skilled in the art to understand the embodiments described herein.

Claims

1. A sensing structure comprising: a tubular element through which a fluid can flow along a single path; an array of sensors disposed along a length of the tubular element, whereby the fluid can flow through each of the sensors; and a sensing circuit electrically connected with each of the sensors and configured to measure a reactance of each of the sensors and determine whether any of the reactances indicates a presence of biological cells in the fluid flowing through the corresponding sensor.

2. The sensing structure of claim 1, wherein, Each sensor includes opposing electrodes located on opposite sides of the tubular element.

3. The sensing structure of claim 1, wherein, Three or more sensors are disposed along the length of the tubular element.

4. The sensing structure of claim 1, the sensors are arranged at uniform intervals along the length of the tubular element.

5. The sensing structure of claim 1, wherein, The sensing circuit is configured to measure at least one of a capacitance and an inductance across the array of sensors.

6. The sensing structure of claim 1, wherein, The sensing circuit is configured to measure at least one of a capacitance and an inductance of each of the sensors.

7. The sensing structure of claim 1, wherein, The sensing circuit is controllable to obtain a dielectric constant of the fluid over a range of operating frequencies when the fluid is free of the biological cells and when the fluid has the biological cells.

8. The sensing structure of claim 7, wherein, The array of sensors and the sensing circuit are calibrated by obtaining a dielectric constant of the fluid over the range of operating frequencies when the fluid has only one type of biological cells.

9. A sensing structure comprising: a bottom wafer; a top wafer; an insulator layer interposed between the bottom wafer and the top wafer and formed to define a channel along which a fluid can flow along a single path; a sensor disposed along a length of the channel, whereby the fluid can flow through each of the sensors; and a sensing circuit electrically connected with each of the sensors and configured to measure at least one of a capacitance and an inductance of each of the sensors and determine whether any of the at least one of the capacitance and the inductance indicates a presence of biological cells in the fluid flowing through the corresponding sensor.

10. The sensing structure of claim 9, wherein, The sensors include reference sensors and sample sensors interleaved along the length of the channel.

11. The sensing structure of claim 10, wherein, Each of the sensors includes a pair of ground-signal-ground (GSG) electrodes on opposite sides of the channel.

12. The sensing structure of claim 10, wherein, The sensing circuit includes probes, each probe including: a pad exposed to an exterior; a tip disposed in electrical contact with a corresponding one of the reference sensors and the sample sensors; and a metallization layer extending through the insulator layer between each of the pad and the tip.

13. The sensing structure of claim 12, wherein, The tip of each probe is disposed in electrical contact with adjacent ones of the reference sensors and the sample sensors.

14. The sensing structure of claim 12, wherein, The probe pairs have overlapping tips.

15. A method of operating a sensing structure for sensing biological cells in a fluid, the method comprising: arranging sensors into an array along a single path; obtaining a baseline reactance of each of the sensors; flowing the fluid along the single path through the sensors in the array; obtaining a test reactance of each of the sensors during the flow of the fluid; and determining whether a difference between the baseline reactance and the test reactance of each of the sensors exists and is indicative of the presence of the biological cells.

16. The method of claim 15, wherein: the obtaining of the baseline reactance and the obtaining of the test reactance each comprise obtaining a capacitance of each of the sensors, and the obtaining of the baseline reactance and the obtaining of the test reactance each comprise obtaining an inductance of each of the sensors.

17. The method of claim 15, further comprising calibrating the sensors over a range of operating frequencies.

18. The method of claim 15, wherein, the obtaining of the baseline reactance comprises: obtaining a first reactance of each of the sensors under empty conditions; and obtaining a second reactance of each of the sensors during the flow of the fluid in the absence of the biological cells.

19. The method of claim 15, wherein, the obtaining of the test reactance of each of the sensors comprises continuing the obtaining in the event of one or more of a determination that a statistically significant number of biological cells are not detected, a determination by data analysis that a sufficient number of detection and identification events are not detected, and a determination that neural network training is not complete.

20. The method of claim 15, further comprising: training a neural network model to identify different types of biological cells.

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