Optical Detection Device with a Protective Pad and Associated Methods

Abstract

This application relates to, but is not limited to, optical detection devices with protective pads and related methods. An optical detection device and related methods are provided. The device may include a reaction structure for containing a reaction solution having a relatively high or low pH and a plurality of reaction sites that produce light emissions. The device may include a device base that includes a plurality of light sensors, device circuitry coupled to the light sensors, and a plurality of light guides that block excitation light but allow light emissions to pass to the light sensors. The device base may also include a cushion layer that extends around each light guide between each light guide and the device circuitry, and a protective layer that is chemically inert with respect to the reaction solution that extends around each light guide between each light guide and the cushion layer. The protective layer prevents the reaction solution passing through the reaction structure and the light guides from interacting with the device circuitry.

Description

[0001] This application is a divisional application of the application with the filing date of December 20, 2018, application number 201811565678.9, and invention title "Optical Detection Device with Protective Pad and Related Method".

[0002] Cross - reference to related applications

[0003] This patent application claims the priority of U.S. Provisional Patent Application No. 62 / 609,889, entitled "Light Detection Devices with Protective Liner and Methods of Manufacturing Same", filed on December 22, 2017, and Dutch Application No. 2020612, entitled "Light Detection Devices with Protective Liner and Methods of Manufacturing Same", filed on March 19, 2018. The entire content of each of the above - mentioned applications is hereby incorporated by reference into this application. Background of the invention

[0004] Various protocols in biological or chemical research involve performing a large number of controlled reactions on a local support surface or within a predefined reaction chamber. Then, a designated reaction can be observed or detected, and subsequent analysis can help identify or reveal the nature of the substances involved in the reaction. For example, in some multiplex assays, an unknown analyte with an identifiable label (such as a fluorescent label) can be exposed to thousands of known probes under controlled conditions. Each known probe can be deposited into a corresponding well of a microplate. Observing any chemical reaction that occurs between the known probe and the unknown analyte within the well can help identify or reveal the nature of the analyte. Other examples of such protocols include known DNA sequencing processes, such as sequencing by synthesis (SBS) or cyclic array sequencing.

[0005] In some conventional fluorescence detection protocols, an optical system is used to direct excitation light onto a fluorescent - labeled analyte and also to detect the fluorescent signal that may be emitted from the analyte. However, such an optical system can be relatively expensive and involves a relatively large bench - top footprint. For example, such an optical system can include an arrangement of lenses, filters, and light sources.

[0006] In other proposed detection systems, the controlled reaction occurs on a local support surface or within a predetermined reaction chamber disposed on an electronic solid-state photodetector or imager (such as a complementary metal-oxide semiconductor (CMOS) detector or a charge-coupled device (CCD) detector) that does not involve large optical components for detecting fluorescence emission. However, such proposed solid-state imaging systems may have some limitations. For example, fluidly delivering reagents (such as fluorescently labeled molecules) in solution to an analyte located on the electronics of such a system can pose challenges. For example, in some cases, the reagent solution may damage the electronics and corrode or otherwise damage components of the electronics. Summary of the Invention

[0007] In one aspect of the present disclosure, there is provided an apparatus. The apparatus includes a reaction structure that forms a plurality of reaction grooves and at least one reaction site. The plurality of reaction grooves are for containing a reaction solution having a pH less than or equal to about 5 or a pH greater than or equal to about 8. The at least one reaction site produces light emission in response to incident excitation light after being treated with the reaction solution. The apparatus further includes a device base positioned below the reaction structure. The device base includes a plurality of light sensors and device circuitry. The device circuitry is electrically coupled to the light sensors to transmit data signals based on photons detected by the light sensors. The device base also includes a plurality of light guides having input regions that receive excitation light and light emission from at least one corresponding reaction groove. The light guides extend from the input regions towards at least one corresponding light sensor into the device base and include at least one filtering material that filters the excitation light and allows the light emission to be transmitted to at least one corresponding light sensor. The apparatus also includes a cushion layer that extends around each light guide and is positioned between each light guide and the device circuitry. The device base further includes a protective layer that extends around each light guide and is positioned between each light guide and the cushion layer. The protective layer prevents the reaction solution passing through the reaction structure and the light guides from interacting with the device circuitry. The protective layer is chemically inert with respect to the reaction solution.

[0008] In some examples, the protective layer abuts the plurality of light guides within the device base. In some such examples, the device circuitry is disposed within a dielectric material layer of the device base, the cushion layer is positioned between the protective layer and the dielectric material layer, and the cushion layer abuts the dielectric material layer.

[0009] In some examples, the protective layer also extends between the top surface of the device base and a gap region of the reaction structure that extends around the reaction grooves. In some such examples, the cushion layer extends between the protective layer and the top surface of the device base.

[0010] In some examples, the protective layer includes silicon dioxide, metal oxide, metal nitride, or a combination thereof. In some examples, the protective layer includes silicon dioxide, silicon oxynitride, silicon monoxide, silicon carbide, silicon oxycarbide, silicon nitrocarbide, metal oxide, metal nitride, or a combination thereof. In some such examples, the pH of the reaction solution is greater than or equal to about 8. In some examples, the pH of the reaction solution is less than or equal to about 5, and the protective layer includes silicon carbide, silicon oxycarbide, silicon nitrocarbide, metal oxide, metal nitride, or a combination thereof. In some examples, the protective layer includes a liquid-impermeable barrier layer. In some examples, the cushion layer is a silicon nitride cushion layer.

[0011] In some examples, the device circuit includes interconnected conductive elements, and the protective layer prevents the reaction solution from oxidizing the conductive elements. In some examples, the thickness of the protective layer is in the range of about 5 nanometers to about 100 nanometers. In some examples, the reaction structure includes at least one reaction site fixed to each of a plurality of reaction grooves, and the reaction solution can initiate a reaction and / or form a reaction product at at least one reaction site that emits light in response to incident excitation light. In some such examples, at least one reaction site includes at least one analyte, and the reaction solution contains at least one fluorescently labeled molecule.

[0012] In some examples, the device circuit of the device base forms a complementary metal oxide semiconductor (CMOS) circuit.

[0013] In another aspect of the present disclosure, a biosensor is provided. The biosensor includes any one of the above devices. The biosensor further includes a flow cell mounted on the device. The flow cell includes a reaction solution and at least one flow channel that is in fluid communication with the plurality of reaction grooves of the reaction structure to direct the reaction solution to the plurality of reaction grooves.

[0014] In another aspect of the present disclosure, a method is provided. The method includes forming a plurality of trenches within a device base, the device base including a plurality of optical sensors and device circuitry, the device circuitry being electrically coupled to the optical sensors to transmit data signals based on photons detected by the optical sensors, the plurality of trenches extending from a top surface of the device base and towards at least one corresponding optical sensor. The method further includes depositing a buffer layer over the device base such that the buffer layer extends at least within the plurality of trenches, and depositing a protective layer over the buffer layer such that the protective layer extends at least within the plurality of trenches. The method further includes filling the plurality of trenches above the deposited protective layer with at least one filtering material to form a plurality of optical waveguides, the at least one filtering material filtering light of at least a first wavelength and allowing light of a second wavelength to pass through the at least one filtering material to reach at least one corresponding optical sensor. The method further includes forming a reaction structure over the plurality of optical waveguides and the protective layer, the reaction structure forming a plurality of reaction grooves corresponding to the at least one optical waveguide and at least one reaction site, the plurality of reaction grooves for containing a reaction solution having a pH less than or equal to about 5 or a pH greater than or equal to about 8, the at least one reaction site emitting light of a second wavelength in response to incident excitation light of a first wavelength after being treated with the reaction solution. The protective layer is chemically inert with respect to the reaction solution.

[0015] In some examples, the protective layer includes silicon dioxide, silicon oxynitride, silicon monoxide, silicon carbide, silicon carbonitride, nitro silicon carbide, metal oxides, metal nitrides, or combinations thereof, and wherein the buffer layer is a silicon nitride buffer layer. In some examples, depositing the buffer layer over the device base further includes depositing the buffer layer above a top surface of the device base, and depositing the protective layer over the device base further includes depositing the protective layer above a portion of the buffer layer that extends above the top surface of the device base.

[0016] In some examples, the method further includes passing a reaction solution having a pH less than or equal to about 5 or a pH greater than or equal to about 8 over the reaction structure.

[0017] It should be recognized that all combinations of the foregoing aspects and additional concepts discussed in greater detail below (assuming these concepts are not mutually inconsistent) are considered to be part of the inventive subject matter disclosed herein.

[0018] These and other objects, features, and advantages of the present disclosure will become apparent from the following detailed description of various aspects of the disclosure in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] These and other features, aspects, and advantages of the present disclosure will become better understood when the following detailed description is read with reference to the accompanying drawings, which are not necessarily drawn to scale, and in which like reference numerals represent like aspects throughout, where:

[0020] Figure 1 Shows a cross-section of a biosensor according to the present disclosure in one example.

[0021] Figure 2 Shows in one example Figure 1 Top view of the detection device of the biosensor in

[0022] Figure 3 Shows in one example Figure 2 Cross-section of a part of the detection device in , which shows a part of the reaction structure and its light guide.

[0023] Figure 4 Shows in one example Figure 3 Enlarged portion of the cross-section in

[0024] Figure 5 Shows in one example Figure 4 Enlarged portion of the cross-section in , where the reaction solution is on the reaction structure.

[0025] Figure 6 Shows in one example during a light detection event Figure 4 Enlarged portion of the cross-section in

[0026] Figure 7 Shows in one example Figure 4 Enlarged portion of the cross-section of , where the reaction structure and the light guide are discontinuous.

[0027] Figure 8 Shows in one example Figure 7 Enlarged portion of the cross-section in , where the reaction structure, the light guide, and its cushion layer are discontinuous.

[0028] Figure 9 Is a flowchart showing a method of manufacturing a light detection device according to the present disclosure in one example.

[0029] Figure 10 Shows in one example forming a trench in the device base of the light detection device.

[0030] Figure 11 Shows in one example in Figure 10 Forming a cushion layer in the trench in the device base in

[0031] Figure 12 Shows in one example in Figure 11 Forming a protective layer above the cushion layer in

[0032] Figure 13 Shows in one example in Figure 12A light guide having a first filter material is formed above the protective layer therein. Detailed implementation mode

[0033] Aspects of the present disclosure, along with certain of its examples, features, advantages, and details, are explained more fully below with reference to the non-limiting examples shown in the accompanying drawings. Descriptions of well-known materials, manufacturing tools, processing techniques, etc. are omitted so as not to obscure relevant details unnecessarily. However, it should be understood that the detailed descriptions and specific examples, while indicating various aspects of the present disclosure, are given by way of illustration only and not by way of limitation. From the present disclosure, various substitutions, modifications, additions, and / or arrangements within the spirit and / or scope of the basic inventive concept will be apparent to those skilled in the art.

[0034] As used throughout this disclosure, approximating language may be applied to modify any quantitative representation that could permissibly vary without resulting in a change in the basic function associated therewith. Thus, a value modified by one or more of the terms, such as "about" or "substantially", is not limited to the precise value specified. For example, these terms may refer to less than or equal to ±5%, such as less than or equal to ±2%, such as less than or equal to ±1%, such as less than or equal to ±0.5%, such as less than or equal to ±0.2%, such as less than or equal to ±0.1%, such as less than or equal to ±0.05%. In some cases, the approximating language may correspond to the precision of the instrument used to measure the value.

[0035] The terms used herein are for the purpose of describing particular examples only and are not intended to be limiting. As used herein, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Additionally, the reference to "example" is not intended to be construed as excluding the existence of additional examples that also include the stated features. Further, unless expressly stated to the contrary, the terms "comprising" (and any form of "comprise", such as "comprises" and "comprising"), "have" (and any form of "have", such as "has" and "having"), "include" (and any form of "include", such as "includes" and "including"), and "contain" (and any form of "contain", such as "contains" and "containing") are used as open-ended linking verbs. As a result, any example that "comprises", "has", "includes", or "contains" one or more steps or elements possesses such one or more steps or elements, but is not limited to possessing only such one or more steps or elements. As used herein, the terms "may" and "may be" indicate the possibility of occurring in a set of circumstances; possessing a particular property, feature, or function; and / or qualify another verb by expressing one or more of the ability, capability, or possibility associated with the qualifying verb. Thus, the use of "may" and "may be" indicates that the modified term is clearly suitable, able, or apt for the indicated ability, function, or use, while allowing for the possibility that in some circumstances, the modified term may sometimes be unsuitable, unable, or inapt. For example, in some cases, an event or ability is expected, while in other cases, the event or ability may not occur, and this distinction is encompassed by the terms "may" and "may be".

[0036] The examples described herein can be used in a variety of biological or chemical processes and systems for academic or commercial analysis. More specifically, the examples described herein can be used in a variety of processes and systems where it is desired to detect events, properties, qualities, or characteristics indicative of a specified reaction. For example, the examples described herein include light detection devices, biosensors, and their components, as well as a biometric system that operates with a biosensor. In some examples, the device, biosensor, and system can include a flow cell and one or more light sensors coupled together (removably or fixedly) in a substantially integral structure.

[0037] The device, biosensor, and biometric system can be configured to perform a plurality of specified reactions that can be detected individually or collectively. The device, biosensor, and biometric system can be configured to perform multiple cycles in which a plurality of specified reactions occur in parallel. For example, the device, biosensor, and biometric system can be used to sequence a dense DNA feature array through iterative cycles of enzymatic manipulation and light or image detection / acquisition. Thus, the device, biosensor, and biometric system (e.g., through one or more cartridges) can include one or more microfluidic channels that deliver reagents or other reaction components in a reaction solution to the reaction sites of the device, biosensor, and biometric system. In some examples, the reaction solution can be substantially acidic, e.g., having a pH less than or equal to about 5, or less than or equal to about 4, or less than or equal to about 3. In some other examples, the reaction solution can be substantially alkaline / basic, e.g., having a pH greater than or equal to about 8, or greater than or equal to about 9, or greater than or equal to about 10. As used herein, the term "acidity" and its grammatical variants refer to a pH value less than about 7, while the terms "basicity", "alkalinity" and their grammatical variants refer to a pH value greater than about 7.

[0038] In some examples, the reaction sites are provided or spaced apart in a predetermined manner, e.g., in a uniform or repeating pattern. In some other examples, the reaction sites are randomly distributed. Each reaction site can be associated with one or more light guides and one or more light sensors that detect light from the associated reaction site. In some examples, the reaction sites are located in reaction grooves or reaction chambers that can at least partially separate the specified reactions therein.

[0039] As used herein, "designated reaction" includes a change in at least one of the chemical, electrical, physical, or optical properties (or mass) of a chemical or biological substance of interest, such as an analyte of interest. In a particular example, the designated reaction is a positive binding event, such as the binding of a fluorescently labeled biomolecule to an analyte of interest. More generally, the designated reaction can be a chemical transformation, chemical change, or chemical interaction. The designated reaction can also be a change in electrical properties. In a particular example, the designated reaction includes the binding of a fluorescently labeled molecule to an analyte. The analyte can be an oligonucleotide, and the fluorescently labeled molecule can be a nucleotide. The designated reaction can be detected when excitation light is directed towards the oligonucleotide having the labeled nucleotide and the fluorophore emits a detectable fluorescent signal. In an alternative example, the detected fluorescence is the result of chemiluminescence or bioluminescence. The designated reaction can also, for example, increase fluorescence by bringing a donor fluorophore close to an acceptor fluorophore (or ) resonance energy transfer (FRET), decrease FRET by separating the donor fluorophore and the acceptor fluorophore, increase fluorescence by separating a quencher from the fluorophore, or decrease fluorescence by co-localizing the quencher and the fluorophore.

[0040] As used herein, "reaction solution", "reaction component", or "reactant" includes any substance that can be used to obtain at least one designated reaction. For example, potential reaction components include, for example, reagents, enzymes, samples, other biomolecules, and buffer solutions. The reaction components can be delivered to the reaction site in solution and / or immobilized at the reaction site. The reaction components can interact directly or indirectly with another substance, such as an analyte of interest immobilized at the reaction site. As described above, the reaction solution can be substantially acidic (i.e., including a relatively high acidity) (e.g., including a pH less than or equal to about 5, a pH less than or equal to about 4, or a pH less than or equal to about 3) or substantially alkaline / basic (i.e., including a relatively high alkalinity / basicity) (e.g., including a pH greater than or equal to about 8, a pH greater than or equal to about 9, or a pH greater than or equal to about 10).

[0041] As used herein, the term "reaction site" is a local region in which at least one specified reaction can occur. A reaction site can include a reaction structure or a support surface of a substrate, on which substances can be immobilized. For example, a reaction site can include a surface of a reaction structure (which can be located in a channel of a flow cell) having reaction components thereon, such as a nucleic acid community thereon. In some such examples, the nucleic acids in the community have the same sequence, which is a cloned copy of, for example, a single-stranded or double-stranded template. However, in some examples, a reaction site can contain only a single nucleic acid molecule, for example, in single-stranded or double-stranded form.

[0042] Multiple reaction sites can be randomly distributed along the reaction structure or arranged in a predetermined manner (e.g., side by side in a matrix, such as in a microarray). A reaction site can also include a reaction chamber or a recess that at least partially defines a spatial region or volume configured to separate a specified reaction. As used herein, the term "reaction chamber" or "reaction recess" includes a defined spatial region of a support structure (which is generally in fluid communication with a flow channel). The reaction recess can be at least partially separated from other regions or spatial regions of the surrounding environment. For example, multiple reaction recesses can be separated from each other by a shared wall, such as a detector surface. As a more specific example, a reaction recess can be a nanowell including an indentation, a pit, a well, a groove, a cavity, or a depression defined by the inner surface of a detection surface, and can have an opening or a pore (i.e., be open-ended), such that the nanowell can be in fluid communication with the flow channel.

[0043] In some examples, the size and shape of the reaction recess of the reaction structure are designed relative to a solid (including a semi-solid) such that the solid can be inserted therein in whole or in part. For example, the size and shape of the reaction recess can be designed to accommodate a capture bead. The capture bead can have cloned amplified DNA or other substances thereon. Optionally, the size and shape of the reaction recess can be designed to receive an approximate number of beads or solid substrates. As another example, the reaction recess can be filled with a porous gel or substance configured to control the diffusion or filtration of fluids or solutions that may flow into the reaction recess.

[0044] In some examples, a light sensor (e.g., a photodiode) is associated with a corresponding reaction site. The light sensor associated with the reaction site is configured to detect light emission from the associated reaction site via at least one light guide when a specified reaction occurs at the associated reaction site. In some cases, multiple light sensors (e.g., several pixels of a light detection or camera device) may be associated with a single reaction site. In other cases, a single light sensor (e.g., a single pixel) may be associated with a single reaction site or a group of reaction sites. Other features of the light sensor, reaction site, and biosensor may be configured such that at least some light is detected directly by the light sensor without being reflected.

[0045] As used herein, "biological or chemical substance" includes biomolecules, samples of interest, analytes of interest, and other compounds. Biological or chemical substances can be used to detect, identify, or analyze other compounds, or as a medium for studying or analyzing other compounds. In certain examples, biological or chemical substances include biomolecules. As used herein, "biomolecule" includes at least one of biopolymers, nucleosides, nucleic acids, polynucleotides, oligonucleotides, proteins, enzymes, polypeptides, antibodies, antigens, ligands, receptors, polysaccharides, carbohydrates, polyphosphates, cells, tissues, organisms, or fragments thereof or any other bioactive compound, such as analogs or mimics of the foregoing substances. In another example, a biological or chemical substance or biomolecule includes an enzyme or reagent used in a coupling reaction to detect another reaction product, such as an enzyme or reagent, e.g., an enzyme or reagent for detecting pyrophosphate in a pyrosequencing reaction. Enzymes and reagents for pyrophosphate detection are described, for example, in U.S. Patent Publication No. 2005 / 0244870A1, which is incorporated herein by reference in its entirety.

[0046] Biomolecules, samples, and biological or chemical substances can be naturally occurring or synthetic and can be suspended in a solution or mixture within a reaction well or region. Biomolecules, samples, and biological or chemical substances can also be bound to a solid phase or gel material. Biomolecules, samples, and biological or chemical substances can also include pharmaceutical compositions. In certain cases, the biomolecules, samples, and biological or chemical substances of interest may be referred to as targets, probes, or analytes.

[0047] As used herein, a "biosensor" includes a device that includes a reaction structure having a plurality of reaction sites configured to detect a specified reaction occurring at or near the reaction sites. The biosensor can include a solid-state light detection or "imaging" device (e.g., a CCD or CMOS light detection device) and optionally a flow cell mounted thereon. The flow cell can include at least one flow channel in fluid communication with the reaction sites. As a specific example, the biosensor is configured to be fluidically and electrically coupled to a bioassay system. The bioassay system can deliver a reaction solution to the reaction sites according to a predetermined protocol (e.g., synthetic sequencing) and perform a plurality of imaging events. For example, the bioassay system can direct the reaction solution to flow along the reaction sites. At least one of the reaction solutions can include four types of nucleotides having the same or different fluorescent labels. The nucleotides can bind to the reaction sites, e.g., bind to corresponding oligonucleotides at the reaction sites. The bioassay system can then irradiate the reaction sites with an excitation light source (e.g., a solid-state light source such as a light-emitting diode (LED)). The excitation light can have one or more predetermined wavelengths, including a range of wavelengths. The fluorescent labels excited by the incident excitation light can provide an emission signal that can be detected by the light sensor (e.g., light of one or more wavelengths different from the excitation light and potentially different from each other).

[0048] As used herein, when used with respect to a biomolecule or a biological or chemical substance, the term "immobilized" includes substantially attaching a biomolecule or a biological or chemical substance to a surface at the molecular level, e.g., attaching to a light detection device or the detection surface of a reaction structure. For example, adsorption techniques (including non-covalent interactions (e.g., electrostatic forces, van der Waals forces, and hydrophobic interfacial dehydration)) and covalent binding techniques (where functional groups or linkers assist in attaching the biomolecule to the surface) can be used to immobilize a biomolecule or a biological or chemical substance to the surface of a reaction structure. Immobilizing a biomolecule or a biological or chemical substance to a surface can be based on the nature of the surface, the liquid medium carrying the biomolecule or biological or chemical substance, and the nature of the biomolecule or biological or chemical substance itself. In some cases, the surface can be functionalized (e.g., chemically or physically modified) to assist in immobilizing the biomolecule (or biological or chemical substance) to the surface.

[0049] In some examples, nucleic acids can be immobilized on a reaction structure, such as on the surface of its reaction recess. In certain examples, the devices, biosensors, bioassay systems, and methods described herein can include the use of natural nucleotides and also the use of enzymes configured to interact with the natural nucleotides. Natural nucleotides include, for example, ribonucleotides or deoxyribonucleotides. Natural nucleotides can be in the form of monophosphates, diphosphates, or triphosphates, and can have a base selected from adenine (A), thymine (T), uracil (U), guanine (G), or cytosine (C). However, it is to be understood that unnatural nucleotides, modified nucleotides, or analogs of the above nucleotides can be used.

[0050] As described above, biomolecules or biological or chemical substances can be immobilized at reaction sites in the reaction recesses of a reaction structure. Such biomolecules or biological substances can be physically held or immobilized within the reaction recess by interference fit, adhesion, covalent bonding, or entrapment. Examples of articles or solids that can be disposed within the reaction recess include polymeric beads, pellets, agarose gels, powders, quantum dots, or other solids that can be compressed and / or retained within the reaction chamber. In some embodiments, the reaction recess can be coated or filled with a hydrogel layer capable of covalently binding DNA oligonucleotides. In a particular example, a nucleic acid superstructure, such as a DNA sphere, can be disposed in or at the reaction recess, for example, by attachment to the inner surface of the reaction recess or by remaining in the liquid within the reaction recess. A DNA sphere or other nucleic acid superstructure can be formed and then disposed in or at the reaction recess. Alternatively, a DNA sphere can be synthesized in situ at the reaction recess. The substance immobilized in the reaction recess can be solid, liquid, or gaseous.

[0051] Figure 1-8 A cross-section of a portion of a biosensor 100 formed according to one example is shown. As shown, the biosensor 100 can include a flow cell 102 directly or indirectly coupled to a light detection device 104. The flow cell 102 can be mounted to the light detection device 104. In the illustrated example, the flow cell 102 is directly fixed to the light detection device 104 by one or more fixing mechanisms (e.g., adhesive, bond, fastener, and the like). In some examples, the flow cell 102 can be removably coupled to the light detection device 104.

[0052] The biosensor 100 and / or the detection device 104 can be configured for biological or chemical analysis to obtain any information or data related thereto. In a particular example, the biosensor 100 and / or the detection device 104 can include a nucleic acid sequencing system (or sequencer) configured for various applications, including but not limited to de novo sequencing, re-sequencing of whole genomes or target genomic regions, and metagenomics. The sequencing system can be configured to perform DNA or RNA analysis. In some examples, the biosensor 100 and / or the detection device 104 are configured to perform a large number of parallel reactions within the biosensor 100 and / or the detection device 104 to obtain information related thereto.

[0053] The flow cell 102 can include one or more flow channels that direct a solution to or towards a reaction site 114 on the detection device 104, as further explained below. The flow cell 102 and / or the biosensor 100 can thus include a fluid / solution storage system (not shown) or be in fluid communication with the fluid / solution storage system, which can store various reaction components or reactants, for example, for performing a specified reaction therein. The fluid storage system can also store fluids or solutions for cleaning or flushing the fluid network and the biosensor 100 and / or the detection device 104 and potentially for diluting reactants. For example, the fluid storage system can include various reservoirs for storing samples, reagents, enzymes, other biomolecules, buffer solutions, aqueous solutions, oils, and other non-polar solutions, and the like. As described above, the fluid or solution provided on the reaction structure 126 can be relatively acidic (e.g., pH less than or equal to about 5) or basic / alkaline (e.g., pH greater than or equal to about 8). Additionally, the fluid storage system can also include a waste reservoir for receiving waste products from the biosensor 100 and / or the detection device 104.

[0054] In the illustrated example, the light detection device 104 includes a device base 125 and a reaction structure 126 covering the device base 125, as Figure 1 and Figure 3-8 shown. In a particular example, the device base 125 includes a plurality of stacked layers (e.g., silicon layers or wafers, dielectric layers, metal-dielectric layers, etc.). The device base 125 can include a sensor array 124 of light sensors 140 and a guiding array of light guides 118, as Figure 3 shown. As Figure 1 and Figure 3-8As shown, the reaction structure 126 may include an array of reaction grooves 108 in which at least one corresponding reaction site 114 is disposed (e.g., immobilized on its surface). In some examples, the light detection device 104 is configured such that each light sensor 140 corresponds to a single light guide 118 and / or a single reaction groove 108 (and potentially is aligned therewith), such that it receives photons only therefrom. However, in other examples, a single light sensor 140 may receive photons through more than one light guide 118 and / or from more than one reaction groove 108. Thus, a single light sensor 140 may form one pixel or more than one pixel.

[0055] As Figure 2 shown, the array of reaction grooves 108 and / or light guides 118 (and potentially light sensors 140) may be arranged in a defined repeating pattern such that at least some of the grooves 108 and / or light guides 118 (and potentially light sensors 140) are equally spaced from each other in a defined position pattern. In other examples, the reaction grooves 108 and / or light guides 118 (and potentially light sensors 140) may be arranged in a random pattern, and / or at least some of the reaction grooves 108 and / or light guides 118 (and potentially light sensors 140) may be variably spaced from each other.

[0056] As Figure 1 and Figure 2 shown, the reaction structure 126 of the detection device 104 may define a detector surface 112 on which a reaction solution may flow and reside, as further explained below. The detector surface 112 of the reaction structure 126 may be the top exposed surface of the detection device 104. The detector surface 112 may include the surfaces of the grooves 108 and an interstitial region 113 extending between and around the grooves 108. As further explained below, the device base 125 of the detection device 104 may include a protective layer 130 that forms a smooth flat (e.g., planar) surface below the support structure, which minimizes surface topography modulation induced in the detector surface 112 and particularly in the interstitial region 113 of the detector surface 112. In a particular example, the interstitial region 113 of the detector surface 112 may be a smooth planar surface portion that prevents a reaction solution and / or any other biological or chemical substance from remaining thereon and / or prevents jump errors. The smoothness and / or flatness of the interstitial region 113 of the detector surface 112 provided by the configuration of the underlying protective layer 130 may be smoother and / or flatter compared to examples without the protective layer 130. Additionally, in some examples, the smoothness and / or flatness of the interstitial region 113 of the detector surface 112 provided by the underlying protective layer 130 may enhance the robustness of the detection device 104 compared to examples without the protective layer 130.

[0057] The detector surface 112 of the optical detection device 104 can be functionalized (e.g., chemically or physically modified in a suitable manner for performing a specified reaction). For example, the detector surface 112 can be functionalized and can include a plurality of reaction sites 114 to which one or more biomolecules are immobilized thereon, as Figure 1 , Figure 3 and Figure 4 shown. As described above, the detector surface 112 can include an array of reaction recesses 108 (e.g., open reaction chambers). Each of the reaction recesses 108 can include one or more of the reaction sites 114. The reaction recesses 108 can be defined, for example, by a variation along the depth (or thickness) of the detector surface 112. In other examples, the detector surface 112 can be substantially planar.

[0058] As Figure 3 and Figure 4 shown, the reaction sites 114 can be distributed in a pattern along the detector surface 112, for example, within the reaction recesses 108. For example, the reaction sites 114 can be positioned in rows and columns along the reaction recesses 108 in a manner similar to a microarray. However, it should be understood that various patterns of the reaction sites 114 can be used. The reaction sites 114 can include biological or chemical substances that emit light signals, as further explained below. For example, the biological or chemical substances of the reaction sites 114 can produce light emission in response to the excitation light 101. In a particular example, the reaction sites 114 include clusters or colonies of biomolecules (e.g., oligonucleotides) immobilized on the detector surface 112 within the reaction recesses 108. The reaction sites 114 can produce light emission in response to incident excitation light after being treated with a reaction solution. For example, the reaction solution can initiate a reaction and / or form reaction products at the reaction sites 114 that produce light emission in response to the excitation light (but possibly not at other reaction sites of the reaction structure 126 of the device 104).

[0059] As Figure 1 shown, in one example, the flow cell 102 includes at least one sidewall and a flow cover 110. The at least one sidewall can be coupled to the detector surface 112 and extends between the flow cover 110 and the detector surface 112. The flow cell 102 can be configured such that a flow channel 119 is formed between the flow cover 110 and the detector surface 112 of the optical detection device 104. In some examples, the flow channel 119 can have a height (extending between the flow cover 110 and the detector surface 112) in the range of about 50 μm to about 400 μm (micrometers), or more specifically, for example, in the range of about 80 μm to about 200 μm. In one example, the height of the flow channel 119 is about 100 μm. As Figure 1As shown, the flow cell 110 may include a material that is transparent to excitation light 101 propagating from outside the biosensor 100 and towards / into the flow channel 119. Note that the excitation light 101 may approach the flow cell 110 from any angle and along the same or different angles.

[0060] The excitation light 101 may be emitted from any illumination source (not shown), which may or may not be part of the assay system, the biosensor 100, or the light detection device 104. In some examples, the illumination system may include a light source (e.g., one or more LEDs), and potentially include a plurality of optical components to illuminate at least the reaction structure 126 of the detection device 104. Examples of light sources may include lasers, arc lamps, LEDs, or laser diodes. The optical components may be, for example, reflectors, dichroic mirrors, beam splitters, collimators, lenses, filters, wedges, prisms, mirrors, detectors, and the like. In a particular example, the illumination system is configured to direct the excitation light 101 into the reaction site 114 within the recess 108 of the reaction structure 126 of the detection device 104. In some examples, the illumination system may emit excitation light 101 within a certain wavelength range, such as, for example, in the range of about 300 nm to about 700 nm, or more specifically, for example, in the range of about 400 nm to about 600 nm. In some examples, the illumination system may emit excitation light 101 at one or more specific wavelengths that excite a biological or chemical substance at the reaction site 108 (e.g., a reaction initiated by the reaction solution and / or a reaction product formed by the reaction solution at the reaction site 114) to emit light emissions of one or more different wavelengths. For example, in one example where the reaction site 108 includes a fluorophore excited by light of a green wavelength, the excitation light may be about 532 nm, and the light emission may be about 570 nm or greater. <{

[0061] Also as Figure 1 shown, the flow cell 110 may include at least one port 120 that is configured to fluidly engage the flow channel 119 and potentially engage other ports (not shown). For example, the other ports may be from a cartridge or workstation that includes a reaction solution or other biological or chemical substances. The flow channel 119 may be configured (e.g., sized and shaped) to direct a fluid or solution, such as a reaction solution, along the detector surface 112.

[0062] Figure 3 and Figure 4 than Figure 1 more detailedly shows the detection device 104. More specifically, Figure 3 and Figure 4A single light sensor 140, a single light guide 118, and associated circuitry 146 are shown. The single light guide 118 is configured to direct and transfer light emissions from at least one reaction site 114 associated therewith toward the light sensor 140, and the associated circuitry 146 is configured to transmit a signal based on the light emissions (e.g., photons) detected by the light sensor 140. It should be understood that other light sensors 140 and associated components of the sensor array 124 ( Figure 1 and 2 ) may be configured in the same or a similar manner. However, it should also be understood that the light detection device 104 need not be manufactured uniformly throughout. Instead, one or more light sensors 140 and / or associated components may be manufactured differently or have different relationships to each other.

[0063] The circuitry 146 may include interconnected conductive elements (e.g., conductors, traces, vias, interconnects, etc.) capable of conducting an electric current (e.g., the transmission of a data signal based on detected photons). For example, in some examples, the circuitry 146 may include a microcircuit arrangement. The light detection device 104 and / or the device base 125 may include at least one integrated circuit having an array of light sensors 140. The circuitry 146 located within the detection device 104 may be configured for at least one of signal amplification, digitization, storage, and processing. The circuitry 146 may collect (and possibly analyze) the detected light emissions and generate a data signal for communicating the detection data to a biometric system. The circuitry 146 may also perform additional analog and / or digital signal processing within the light detection device 104.

[0064] The device base 125 and the circuitry 146 may be manufactured using an integrated circuit manufacturing process, such as a process for manufacturing a charge-coupled device or circuit (CCD) or a complementary metal-oxide semiconductor (CMOS) device or circuit. For example, as Figure 3 shown, the device base 125 may be a CMOS device that includes a plurality of stacked layers, the plurality of stacked layers including a sensor base 141 which, in some examples, may be a silicon layer (e.g., a wafer). The sensor base 141 may include the light sensors 140 and gates 143 formed thereon. The gates 143 may be electrically coupled to the light sensors 140. When the light detection device 104 is configured as Figure 3 shown, the light sensors 140 may be electrically coupled to the circuitry 146 through, for example, the gates 143.

[0065] At least some of the circuitry 146 may be disposed within a device base layer of the device base 125 of the detection device 104, and each of the optical waveguides 118 may extend through / into the device base layer. In some examples, each of the base layers in the base layer may include interconnecting conductive elements that form at least a portion of the device circuitry 146, and a dielectric material 142 adjacent (and potentially surrounding) the conductive elements of the circuitry 146, as Figure 3 shown. The conductive elements of the circuitry 146 may be embedded within the dielectric material 142. Also as Figure 3 shown, the optical waveguides 118 may extend through the dielectric material 142 and may be spaced apart from the circuitry 146. A variety of metal elements and / or dielectric materials may be used, such as those suitable for integrated circuit fabrication (CMOS fabrication). For example, in some examples, the conductive elements / circuitry 146 may be metal elements, such as, for example, W (tungsten) elements, Cu (copper) elements, Al (aluminum) elements, or combinations thereof (although it should be understood that other materials and configurations may be used). In some examples, the dielectric material may be SiO2 (although it should be understood that other materials and configurations may be used).

[0066] As used herein, unless otherwise specified, the term "layer" is not limited to a single continuous body of material. For example, the device layer of the sensor substrate 141 and / or the device base 125 may include multiple sub-layers of different materials and / or may include coatings, adhesives, and the like. Additionally, one or more of the layers (or sub-layers) may be modified (e.g., etched, deposited with materials, etc.) to provide the features described herein.

[0067] As Figure 3 and Figure 4As shown, the reaction structure 126 may include one or more layers forming reaction grooves 104 extending therein. The reaction structure 126 may extend along the top outer surface of the device base 125. In the illustrated example, the reaction structure 126 is deposited directly along the top outer surface of the first liner layer 154 and the top outer surface of the first (and potentially second) filter material 116 of the device base 125, as further described below. However, in other examples, an intermediate layer may be disposed between the reaction structure 126 and the device base 125. The reaction structure 126 may include one or more materials configured to allow the excitation light signal 101 and the light signal emitted from the reaction site 114 (after treatment with the reaction solution) within the groove 108 to pass therethrough and enter the openings 158 of one or more light guides 118 corresponding to a particular reaction groove 108. In some examples, the reaction structure 126 may include one or more layers or other features that prevent crosstalk or "sharing" of the emitted light from a particular reaction site 114 / reaction groove 108 to non-corresponding sensors 140.

[0068] The reaction structure 126 may include multiple different layers, as Figure 3 and Figure 4 shown. In the illustrated example, the reaction structure 126 may include a first reaction layer 160 that extends (directly or indirectly) above the device base 125 (e.g., above the first liner layer 154) and the openings 158 of the light guides 118 of the device base 125 (e.g., the first (and potentially second) filter material 116), as Figure 3 and Figure 4 shown. Also as Figure 3 and Figure 4 shown, in the illustrated example, the reaction structure 126 further includes a second layer 162 that extends (directly or indirectly) above the first layer 160. The reaction structure 126 of the illustrated example further includes a third layer 164 that extends (directly or indirectly) above the second layer 162 and a fourth layer 166 that extends (directly or indirectly) above the third layer 164. The reaction groove 108 may extend at least into the third layer 164.

[0069] As Figure 3 and Figure 4 shown, the fourth layer 166 may form the inner surface (e.g., sidewall and bottom wall) of the reaction groove 108 by extending above an indentation (e.g., cavity or void) in the third layer 164. As Figure 3 and Figure 4As shown, the fourth layer 166 and potentially the second layer 162 can form the detector surface 112. In some cases, the fourth layer 166 and potentially the second layer 162 can be configured to provide a solid surface that allows chemicals, biomolecules, or other analytes of interest to be immobilized thereon. For example, each of the reaction sites 114 can include a cluster of biomolecules immobilized to the detector surface 112, which can include the fourth layer 166 and possibly the second layer 162. Thus, the fourth layer 166 and potentially the second layer 162 can include materials that allow the reaction sites 114 to be immobilized thereto. The first layer 160 and the fourth layer 166 (and potentially the second layer 162 and the third layer 164) can include materials that are at least substantially transparent to the excitation light 101 and the emission light from the reaction sites 114. Additionally, the fourth layer 166 and potentially the second layer 162 can be physically or chemically modified to facilitate the immobilization of biomolecules and / or to facilitate the detection of light emission.

[0070] For example, and as Figure 3 and Figure 4 In the illustrated example shown, the first layer 160 and the third layer 164 can include a first material, and the second layer 162 and the fourth layer 166 can include a second material different from the first material. In some such examples, the first material is SiN and the second material is TaO. However, the reaction structure 126 can include different layers (e.g., different layers, fewer layers, and / or additional layers) and / or different materials.

[0071] As Figure 3 and Figure 4 As shown, the device base 125 of the detection device 104 can include a first shielding layer 150 that extends (directly or indirectly) over the stacked layers of the device base 125 (e.g., the metal-dielectric layers), such as over the dielectric material 142 and the conductive circuit components 146. The first shielding layer 150 can include a material configured to block, reflect, and / or significantly attenuate the excitation light 101 and / or the light emission from the reaction sites 114 (e.g., the optical signal propagating from the flow channel 118). By way of example only, the first shielding layer 150 can include tungsten (W).

[0072] The first shielding layer 150 may include at least one hole therethrough, and the at least one hole is at least partially aligned with at least one corresponding light guide 118. The first shielding layer 150 may include an array of such holes. In some examples, the first shielding layer 150 may extend completely around the holes therein. Thus, the light signal from the excitation light 101 and / or the light emission from the reaction site 114 may be blocked, reflected, and / or significantly attenuated to prevent the light signal from passing through the device base 125 outside the light guide 118 and being detected by the light sensor 140. In some examples, the first shielding layer 150 extends continuously between adjacent light guides 118 and / or the openings extending thereto. In some other examples, the first shielding layer 150 does not extend continuously between adjacent light guides 118 and / or the openings extending thereto, such that one or more other openings are present in the first shielding layer 150, and the one or more other openings may allow the excitation light 101 and / or the light emission from the reaction site 114 to pass therethrough.

[0073] In some examples, the device base 125 of the detection device 104 may include (directly or indirectly) a second shielding layer 152 extending above the first shielding layer 150, as Figure 3 and Figure 4 shown. The second shielding layer 152 may include an anti-reflection material and / or a material that prevents contamination of the portion below the device base 125. By way of example only, the second shielding layer 152 may include SiON. In some examples, the second shielding layer 152 may be configured to prevent interaction between, for example, contaminated sodium and the conductive (e.g., metal) components of the first shielding layer 150, the dielectric material 142, and / or the device circuitry 146. In some examples, the second shielding layer 152 may mimic the configuration of the first shielding layer 150. For example, the second shielding layer 152 may include at least one hole therethrough, and the at least one hole is at least partially aligned with at least one light guide 118, as Figure 3 and Figure 4 shown. The second shielding layer 152 may include an array of such holes. In some examples, the second shielding layer 152 may extend around the holes therein. In some examples, the second shielding layer 152 extends continuously between adjacent light guides 118 and / or the openings extending thereto. In some other examples, the second shielding layer 152 does not extend continuously between adjacent light guides 118 and / or the openings extending thereto, such that one or more other holes are present in the second shielding layer 152, as Figure 3 and Figure 4 shown.

[0074] In some examples, the light detection device 104 may include a cushion layer 154 that extends above the device base 125 and around the light guides 118, as Figure 3 and Figure 4As shown. The liner layer 154 can be a continuous conformal layer formed on the device base 125. The liner layer 154 can be chemically reactive with respect to the reaction solution. For example, due to the composition of the reaction solution (e.g., water and / or oil) and / or a relatively high acidity (e.g., pH equal to or less than about 5) or a relatively high alkalinity (e.g., pH equal to or greater than about 8), the reaction solution can chemically react with the material of the liner layer 154 when exposed to the material of the liner layer 154, and cause the material to dissolve or otherwise separate (i.e., etch the liner layer 154). As the exposure time progresses, the reaction solution can thus etch through the liner layer 154 and ultimately interact with the device circuitry 146, and corrode the device circuitry 146 or otherwise interfere with the function of the device circuitry 146. For example, the liner layer 154 can be a silicon nitride layer (or otherwise include SiN), and a relatively high-acidity or -alkalinity reaction solution may tend to etch SiN when exposed to SiN. In this way, the SiN liner layer 154 may be ineffective in preventing the reaction solution from etching through the SiN liner layer 154 and ultimately interacting with the device circuitry 146 (e.g., corroding the conductive (e.g., metal) components of the device circuitry 146). Other materials forming the liner layer 154 are similarly chemically reactive with respect to the reaction solution, e.g., due to their composition and / or relatively high acidity or alkalinity, and thus cannot prevent the reaction solution from etching through the liner layer 154 over time.

[0075] The liner layer 154 can have no defined holes. However, the liner layer 154 can include at least one internal discontinuity, pore, crack, fracture, or the like that allows a liquid or solution, e.g., the reaction solution, to flow through the liner layer 154, as further explained below. For example, the density of the liner layer 154 can be relatively low such that its internal discontinuities form a path through the liner layer 154 through which the reaction solution can reach the dielectric material 142 and ultimately the conductive (e.g., metal) components of the device circuitry 146. In this way, the liner layer 154 may be ineffective in preventing the reaction solution from passing through the liner layer 154 and ultimately interacting with the device circuitry. In some examples, due to its density or internal discontinuities, the liner layer 154 may not be liquid-impermeable.

[0076] In the illustrated example, the cushion layer 154 extends between the second shielding layer 152 and the protective layer 130 on the top portion of the device base 125, and extends along the light guide 118 between the dielectric material layer 142 and the protective layer 130. The cushion layer 154 can be configured as an anti-reflection layer or a reflective layer (e.g., to ensure that light emitted from the reaction site 114 passes through the light guide 118), a contamination prevention layer (e.g., to prevent sodium contamination into the device base 125), and / or an adhesive layer (e.g., to bond the filter material 116 of the light guide 118 to the dielectric material 142). In some examples, the cushion layer 154 can be configured as a contamination prevention layer to prevent any ionic substances from penetrating into the device layers (e.g., metal-dielectric layers). In some examples, the cushion layer 154 includes SiN. In some examples, the cushion layer 154 includes a SiN layer.

[0077] As Figure 3 and 4 shown, the cushion layer 154 can have a substantially uniform thickness. In other examples, the thickness of the cushion layer 154 can vary. For example, the portion of the cushion layer 154 that extends above the top portion of the device base 125 can be a first thickness, and the portion of the cushion layer 154 that extends around the light guide 118 can be a second thickness that is thicker or thinner than the first thickness. As another example, the thickness of the portion of the cushion layer 154 that extends around the light guide 118 can vary along the depth within the device base 125 (e.g., can taper as the depth into the device base 125 increases). In some examples, the thickness of the cushion layer 154 can be in the range of about 10 nm to about 100 nm. In the illustrated example, the cushion layer 154 is about 50 nm thick.

[0078] As Figure 3 shown in, the device base 125 can further include a second cushion layer 155 formed within the device layer of the device base 125 and below the light guide 118. The second cushion layer 155 can be substantially similar or identical to the cushion layer 154, but for its position within the device base 125. In some examples, the second cushion layer 155 can extend along the bottom of the light guide 118 directly below the protective layer 130, as Figure 3 shown in. In this way, except for the opening 158 of the light guide 118 below the groove 108, the cushion layer 154 and the second cushion layer 155 can completely surround the light guide 118. The second cushion layer 155 can form the bottom of the light guide 118.

[0079] As discussed above, the device base 125 of the detection device 104 can include a protective cushion layer 130 positioned between each light guide 118 and the device circuit 146, as Figure 3 and Figure 4As shown. The protective layer 130 may extend (either directly or indirectly) above the cushion layer 154 on top of the device base 125 and along the optical waveguide 118, as Figure 3 and Figure 4 shown. In some other examples (not shown), the protective layer 130 may not extend (either directly or indirectly) above the top of the device base 125 below the reaction structure 126, and may only extend along / around the optical waveguide 118 within the device base 126 (i.e., only be positioned between the dielectric material 142 and the filter material 116).

[0080] Except for its opening 158, the protective layer 130 may completely surround the filter material 116 of the optical waveguide 118. For example, the protective layer 130 may extend around the side surface of the optical waveguide 118 and below the optical waveguide 118 (between the cushion layer 154 and the second cushion layer 155 and the filter material 116). The protective layer 130 may also be provided on the device base 125 (e.g., directly above the cushion layer 154) and on the reaction structure 126. The protective layer 130 may thus also be provided above the top of the device base 125 and be positioned between the device base 125 and the reaction structure 126.

[0081] The protective layer 130 may be a continuous coating. The protective layer 130 may not have predefined or deliberately formed holes or other voids that would allow a liquid or solution, such as a reaction solution, to flow through. The protective layer 130 may also not have any internal discontinuities, pores, cracks, fractures, or the like that would allow a liquid or solution, such as a reaction solution, to flow through it, or may prevent their formation, as further explained below. The protective layer 130 may thus be a liquid-impermeable barrier. A liquid-impermeable layer herein refers to a layer that can prevent any liquid or solution (such as a reaction solution) from passing through it, for example, preventing at least about 99 vol% of the reaction solution in contact with the protective layer 130 at about atmospheric pressure from passing through it. The protective layer 130 may also be chemically inert with respect to the reaction solution, such that when the reaction solution contacts the protective layer 130, the reaction solution (as described above, which may include a relatively high acidity or a relatively high alkalinity) does not etch the protective layer 130 at about 100 degrees Celsius and about atmospheric pressure, or etches less than about one (1) angstrom of the thickness of the protective layer 130 per hour For example, the composition of the protective layer 130 may not chemically react with the composition of the reaction solution (which may include a relatively high acidity or a relatively high alkalinity), or may only chemically react to a relatively small extent, such that when the reaction solution contacts the protective layer 130, the reaction solution does not etch the protective layer 130 at about 100 degrees Celsius and about atmospheric pressure or etches less than about one (1) angstrom of the thickness of the protective layer 130 per hour The liner layer 154 may thus include an etch-resistant layer relative to the reaction solution (which may include, for example, a pH equal to or less than about 5 or a pH equal to or greater than about 8) to prevent the reaction solution from penetrating therethrough (over time) and ultimately interacting with the device circuitry 146 and corroding the device circuitry 146 or otherwise interfering with the function of the device circuitry 146. The protective layer 130 is thus configured to prevent a liquid or solution (such as the reaction solution) that can reach the protective layer 130 through the reaction structure 126 or through the filter material 116 of the reaction structure 126 and the light guide 118 from interacting with the device circuitry 146 (and the liner layer 154 (if provided) and the dielectric material 142).

[0082] The thickness of the protective layer 130 may vary. For example, the portion of the protective layer 130 that extends above the top of the device base 125 may be a first thickness, and the portion of the protective layer 130 that extends around and / or beneath the light guide 118 may be a second thickness that is thicker or thinner than the first thickness. As another example, the thickness of the portion of the protective layer 130 that extends around the light guide 118 may vary along the depth of the light guide 118 within the device base 125. In such an example, the thickness of the portion of the protective layer 130 that extends around the light guide 118 may taper (i.e., narrow or thin) as it extends from the opening 158 of the light guide 118 into the device base 125. The protective layer 130 may be a conformal coating. In Figure 3 the illustrated example shown, the protective layer 130 has a substantially uniform thickness. In some examples, the thickness of the liner layer 154 may be in the range of about 10 nm to about 1 micron, in the range of about 5 nm to about 100 nm, or in the range of about 50 nm to about 100 nm. In the illustrated example, the liner layer 154 is about 50 nm thick.

[0083] The protective layer 130 can comprise any material such that it prevents any solution or liquid, such as a reaction solution, that might penetrate the reaction structure 126, or the reaction structure 126 and the light guide 118, from interacting with the device circuitry 146, and allows light emitted from the reaction site 114 (after treatment with the reaction solution) to pass through the protective layer 130 and reach at least one corresponding light sensor 140 (via at least one corresponding light guide 118). For example, the protective layer 130 can comprise any material that allows light emitted from the reaction site 114 and not filtered by the filtering material 116 to pass therethrough and that is chemically inert to the reaction solution. For example, the protective layer 130 can comprise any material that does not chemically react with the reaction solution (which can comprise, for example, a pH equal to or less than about 5 or a pH equal to or greater than about 8) or that reacts only to a relatively small extent such that when the reaction solution contacts the protective layer 130, the reaction solution does not etch the protective layer 130 or etches less than about one (1) angstrom of the thickness of the protective layer 130 per hour at about 100 degrees Celsius and at about atmospheric pressure. For example, the protective layer 130 can comprise at least one oxide, at least one nitride, or a combination thereof. In some examples, the protective layer 130 can comprise silicon dioxide, a metal oxide, a metal nitride, or a combination thereof. In some examples, the protective layer 130 can comprise silicon dioxide, silicon oxynitride, silicon monoxide, silicon carbide, silicon oxycarbide, nitrided silicon carbide, a metal oxide, a metal nitride, or a combination thereof. In some examples, the pH of the reaction solution is greater than or equal to about 8, and the protective layer 130 comprises silicon dioxide, silicon oxynitride, silicon monoxide, silicon carbide, silicon oxycarbide, nitrided silicon carbide, a metal oxide, a metal nitride, or a combination thereof. In some examples, the pH of the reaction solution is less than or equal to about 5, and the protective layer 130 comprises silicon carbide, silicon oxycarbide, nitrided silicon carbide, a metal oxide, a metal nitride, or a combination thereof. Note that the thickness, formation process, and material of the protective layer 130 can be considered and configured (independently or jointly) such that the protective layer 130 prevents any solution or liquid, such as a reaction solution, that might penetrate the reaction structure 126, or the reaction structure 126 and the light guide 118, from ultimately interacting with the device circuitry 146 (and the liner layer 154 (if provided) and the dielectric material 142).

[0084] As discussed above, the light guide 118 can extend from the opening 158 into the device base 125, for example, through the dielectric material layer 142 and towards at least one light detection sensor 140. In a particular example, the light guide 118 is elongate and extends from near at least one corresponding reaction recess 108 (from its aperture 158) towards at least one corresponding light sensor 140 within the sensor base 141. The light guide 118 can extend longitudinally along a central longitudinal axis. The light guide 118 can be configured in a three-dimensional shape, such as substantially cylindrical or frustoconical with a circular opening 158, which allows and / or facilitates light emitted from the reaction sites 114 of at least one corresponding reaction recess 108 to reach at least one corresponding light sensor 140. The longitudinal axis of the light guide 118 can extend through the geometric center of the cross-section. However, in alternative examples, other geometries can be used. For example, the cross-section of the light guide 118 can be substantially square or octagonal.

[0085] The light guide 118 can include a filtering material 116 that is configured to filter the excitation light 101 or a wavelength range that includes the wavelength of the excitation light 101, and allow light emission (or a wavelength range that includes the wavelength of the light emission) from at least one reaction site 114 of at least one corresponding reaction recess 108 to pass through the filtering material 116 and propagate towards at least one corresponding light sensor 140. The light guide 118 can be, for example, an absorption filter (such as an organic absorption filter) such that the filtering material 116 absorbs a specific wavelength (or wavelength range) and allows at least one predetermined wavelength (or wavelength range) to pass through the filtering material 116. By way of only one example, the excitation light can be about 532 nm, and the light emission from at least one reaction site 114 can be about 570 nm or greater, and thus the filtering material 116 can absorb light having a wavelength of about 532 nm or less than about 570 nm, and allow light having a wavelength of about 570 nm or greater to pass through the filtering material 116. Each of the light guides 118 in the array can include substantially the same filtering material 116, or different light guides 118 can include different filtering materials 116.

[0086] Thus, each light guide 118 can be configured relative to the surrounding material of the device base 125 (e.g., the dielectric material 142) to form a light guide structure. For example, the light guide 118 can have a refractive index of at least about 2. In certain examples, the light guide 118 is configured such that the optical density (OD) or absorbance of the excitation light is at least about 4 OD. More specifically, the filtering material 116 of the light guide 118 can be selected, and the size of the light guide 118 can be designed to achieve at least about 4 OD. In a more specific example, the light guide 118 can be configured to achieve at least about 5 OD, or at least about 6 OD.

[0087] Initially, the reaction sites 114 of one or more reaction grooves 108 of the reaction structure 126 of the device 104 or the biosensor 100 may not include a specified reaction, which is typically indicated by the absence of shading / pattern in Figure 4 . As discussed above, the reaction sites 114 may include biological or chemical substances immobilized on the detector surface 112, or more specifically, biological or chemical substances immobilized on the base and / or side surfaces of the reaction grooves 108. In a particular example, the reaction sites 114 are located near the openings 158 of at least one corresponding light guide 118 such that after a specified reaction has occurred by treating with a reaction solution, the pre-specified light emission emitted from the reaction sites 114 propagates through the reaction structure 126, through the openings 158 of at least one corresponding light guide 118 and the filter material 116, through the protective layer (and potentially through the first cushion layer 154 and the second cushion layer 155), and reaches at least one corresponding light sensor 140.

[0088] The biological or chemical substances of a single reaction site 114 may be similar or identical (e.g., a community of analytes (e.g., oligonucleotides) having a common sequence). However, in other examples, a single reaction site 114 and / or the reaction grooves may include different biological or chemical substances. Before the specified reaction, the reaction sites 114 may include at least one analyte (e.g., an analyte of interest). For example, the analyte may be an oligonucleotide or a community thereof (e.g., an oligonucleotide of interest). The oligonucleotide may have an effective common sequence and bind to a predetermined or specific fluorescently labeled biomolecule such as a fluorescently labeled nucleotide.

[0089] However, before the specified reaction, the fluorophore of the fluorescently labeled biomolecule is not incorporated or bound to the biological or chemical substance (e.g., oligonucleotide) at the reaction site 114, as Figure 4 shown in. To effect the specified reaction (i.e., bind the fluorescently labeled biomolecule to the biological or chemical substance of the reaction site 114), the flow cell may provide a flow of the reaction solution 170 to the reaction structure 126, as Figure 5As shown. The reaction solution can include one or more sequencing reagents for, e.g., DNA grafting, clustering, cleaving, incorporating, and / or reading. However, the reaction solution 170 can be any solution. In some examples, the reaction solution 170 can include a liquid. For example, the reaction solution 170 can be an aqueous solution and / or can consist of oil; however, it should be understood that the reaction solution 170 can include any other liquid. The reaction solution 170 can include one or more components that tend to react with the circuit 146, corrode the circuit 146, dissolve the circuit 146, degrade the circuit 146, or otherwise render the circuit 146 inoperable or unable to function effectively as a circuit (i.e., transmit signals or electrons). For example, if the aqueous solution interacts with the circuit 146, the aqueous solution will tend to oxidize the metal portion of the circuit 146.

[0090] In one example, the reaction solution 170 contains one or more nucleotide types, at least some of which are fluorescently labeled, and the reaction solution 170 also contains one or more biomolecules, such as polymerase, which incorporates the nucleotides into a growing oligonucleotide at the reaction site 114, thereby labeling the oligonucleotide with the fluorescently labeled nucleotides. In such an embodiment, the flow cell can provide a wash solution to remove any free nucleotides that have not been incorporated into the oligonucleotide. Then, the reaction site 114 can be irradiated with excitation light 101 of at least a first wavelength, causing fluorescence of a second wavelength and / or a third wavelength at those reaction sites 114 where the fluorescently labeled nucleotides have been incorporated. The reaction sites 114 that have not incorporated the fluorescently labeled nucleotides do not emit light when irradiated with the incident excitation light 101.

[0091] As Figure 5 shown in the example shown, the reaction solution 170 can be disposed within the reaction recess 108 to effect a specified reaction of at least one fluorescently labeled molecule binding to or incorporating with the biological or chemical substance at the reaction site 114. In some examples, the biological or chemical substance at the reaction site 114 can be an analyte, and the fluorescently labeled molecule can include at least one fluorophore that binds to or incorporates with the analyte. In such an example, the analyte can include an oligonucleotide, and the at least one fluorescently labeled molecule includes a fluorescently labeled nucleotide.

[0092] When the biological or chemical substances (e.g., oligonucleotides) at reaction site 114 are similar or identical, such as having a common sequence, reaction site 114 can be configured to produce a common light emission after a specified reaction, and the excitation light 101 is absorbed by the fluorescently labeled molecules that bind to or incorporate with it from reaction solution 170. When the biological or chemical substances (e.g., oligonucleotides) at reaction site 114 are dissimilar or different, such as having different sequences, reaction site 114 can be configured to produce different light emissions after a specified reaction, and the excitation light 101 is absorbed by the fluorescently labeled molecules that bind to or incorporate with it from reaction solution 170. The filter material 116 of light guide 118 can be selected or configured to allow any such light emissions to propagate through it and reach light sensor 140, but prevent other such light emissions and / or excitation light from propagating through it to light sensor 140.

[0093] As Figure 6 shown, after reaction solution 170 has interacted with the biological or chemical substances (e.g., oligonucleotides) at reaction site 114, the specified reaction has occurred such that reaction site 114 includes fluorescently labeled molecules, such as fluorophores, which emit light of a predetermined wavelength or a predetermined wavelength range when excited by excitation light 101 (i.e., when excitation light 101 is incident on reaction site 114). Thus, excitation light 101 can thereby be configured based on the fluorescently labeled molecules of reaction solution 170 (and vice versa) and / or the reaction initiated by reaction solution 170 at reaction site 114 and / or the reaction products formed by reaction solution 170 at reaction site 114. As Figure 6 shown, when excited by excitation light 101 after the specified reaction has occurred by treatment with reaction solution, reaction site 114 can emit a light signal 172 having a wavelength different from that of excitation light 101.

[0094] The emitted light 172 from reaction site 114 (after treatment with reaction solution) can travel in all directions (e.g., isotropically), such that, for example, a portion of light 172 is directed into at least one corresponding light guide 118, and a portion of light 172 is directed into flow channel 119 or reaction structure 126, as Figure 6 shown. For the portion that is transmitted into light guide 118, device 104 (e.g., its light guide 118) is configured to facilitate the detection of photons by at least one corresponding light sensor 140. Specifically, the emitted light 172 from reaction site 114 that passes through the opening of the corresponding light guide 118 will propagate through its filter material 116 to light sensor 140. However, excitation light 101 will be absorbed by filter material 116 or otherwise prevented from propagating through light guide 118 to light sensor 140, as Figure 6As shown in. The device circuitry 146 electrically coupled to the photosensor 140 transmits data signals based on photons detected by the photosensor 140. In this way, during a light detection event, only the specified reaction carried out by treating with a reaction solution at the reaction site 114 will cause the emitted light 172 to be detected by the photosensor 140.

[0095] As Figure 6 As shown in, the transfer of the emitted light 172 from the reaction site 114 into a portion of at least one corresponding light guide 118 can propagate directly through its filter material 116 and propagate to at least one corresponding photosensor 140. For example, at least most of the emitted light 172 from the reaction site 114 entering at least one corresponding light guide 118 via the opening 158 can be transferred directly (e.g., linearly or substantially linearly) through the filter material 116 to reach at least one corresponding photosensor 140. A small amount of the emitted light 172 from the reaction site 114 that is transferred into at least one corresponding light guide 118 can travel at an angle such that it passes through the protective layer 130, the cushion layer 154, and into the dielectric material layer 142. This light can be reflected by the circuitry 146 or other metal or reflective structures embedded within the dielectric material layer 142 and potentially returned to the corresponding light guide 118 (and potentially to at least one corresponding photosensor 140). In some examples, the protective layer 130 and / or the cushion layer 154 can be transparent to light, e.g., at least transparent or substantially transparent to the emitted light 172 from the reaction site 114.

[0096] Figure 7 and Figure 8 illustrates an example of the device 104 that includes cracks or other discontinuities 178 in the reaction structure 126 and the filter material 116 of the light guide 118. As Figure 7 and Figure 8 As shown in, the reaction structure 126, and potentially the filter material 116 of at least one light guide 118, can include cracks or other discontinuities 178 that extend from the detection surface 112 to the protective layer 130. The discontinuities 178 can extend from the detection surface 112 through the reaction structure 126 to the protective layer 130, and / or from the detection surface 112 through the reaction structure 126 and the filter material 116 to the protective layer 130. Thus, the discontinuities 178 can allow solution or liquid to flow from the detection surface 112 into the detection device 104 and interact with the protective layer 130.

[0097] Note that the discontinuous portion 178 or other paths may not be defined and / or continuous as depicted for the discontinuous portion 178. Instead, the discontinuous portion 178 represents any path through which a liquid or solution can (i.e., from the detection surface 112) pass through the reaction structure 126 to the protective layer 130. For example, any path extending from the detection surface 112 through the reaction structure 126 (e.g., extending through the first layer 160, the second layer 162, the third layer 164, and the fourth layer 166 (if present)) to the protective layer 130 may ultimately allow a liquid or solution (e.g., the reaction solution) to interact with the protective layer 130. As another example, any path extending from the detection surface 112 through the reaction structure 126 (e.g., extending through the first layer 160, the second layer 162, the third layer 164, and the fourth layer 166 (if present)) and at least one light guide 118 (e.g., extending through the opening 158 and the filter material 116) to the protective layer 130 may ultimately allow a liquid or solution (e.g., the reaction solution) to interact with the protective layer 130. The discontinuous portion 178 represents any such path.

[0098] The discontinuous portion 178 extending through the reaction structure 126 and / or extending through the reaction structure 126 and at least one light guide 118 can be formed by any process or mechanism. For example, the discontinuous portion 178 extending through the reaction structure 126 and / or extending through the reaction structure 126 and at least one light guide 118 can be formed, for example, during the manufacturing stage of the device 104, and / or during the use of the device 104. As a particular mode of formation, the discontinuous portion 178 may be caused by different coefficients of thermal expansion of the materials of the device 104, which can cause the discontinuous portion 178 to form during the manufacturing stage of the device 104 and / or during the use of the device 104. As another example, the discontinuous portion 178 may be formed by errors in the formation process of the reaction structure 126 and / or the light guide 118, or may occur naturally from the formation process of the reaction structure 126 and / or the light guide 118. As yet another example, the discontinuous portion 178 may be formed by the reaction solution or any other liquid or solution reacting with the reaction structure 126 and / or the light guide 118 and etching through the reaction structure 126 and / or the light guide 118. However, these are just some examples of the modes of formation of the discontinuous portion 178, and the discontinuous portion 178 can be formed by any mode of operation.

[0099] Also as Figure 8As shown and discussed above, the liner 154 can include a discontinuous portion 179 that extends through the liner 154 and permits solution or liquid to flow through the liner 154. The discontinuous portion 179 of the liner 154 can be a relatively small internal discontinuity, pore, crack, or the like. For example, the discontinuous portion 179 of the liner 154 may be created during the manufacturing phase of the liner 154 or device 104 and / or during use of the device 104. For example, the discontinuous portion 179 of the liner 154 may be caused by different coefficients of thermal expansion of the materials of the liner 154 and other parts of the device 104. As another example, the discontinuous portion 179 of the liner 154 may be caused by its formation process. In some examples, the discontinuous portion 179 of the liner 154 may be created by a liquid or solution interacting with the liner 154 and eroding, corroding, or otherwise degrading the liner 154 (thereby permitting the liquid or solution to pass through). However, these are just some examples of the causes of the discontinuous portion 179 of the liner 154, and any discontinuous portion 179 can be formed by any mode of operation. In some examples, the liner 154 can include a material that chemically reacts with the reaction solution such that the reaction solution will etch through the liner 154 (and ultimately degrade the circuit 146). In some such embodiments, the liner 154 may or may not have a discontinuous portion 179.

[0100] When a discontinuous portion 178 is present and the reaction solution 170 (or any other liquid or solution) is introduced onto the reaction structure 126 (e.g., disposed above the detection surface 112 and within the reaction recess 108), the reaction solution 170 (or other liquid or solution) can be able to flow, wick, penetrate, or otherwise travel within / through the discontinuous portion 178 and potentially through the filter material 116 of the light guide 118 and through the reaction structure 126, as Figure 8 shown. Additionally, as also shown in Figure 8As shown, if there is no protective layer 130, the discontinuous portion 179 of the underlayer 154 will allow the penetrating reaction solution 170 (or other liquid or solution) to continue to travel through the detection device 104 to the dielectric material 142 and ultimately interact with the circuit 146. In another example, the penetrating reaction solution 170 (or other liquid or solution) can chemically react with the underlayer 154 and etch through the underlayer 154, continue to travel through the detection device 104 to the dielectric material 142, and ultimately interact with the circuit 146. As described above, the reaction solution 170 can be relatively highly acidic (e.g., pH equal to or less than about 5) or relatively highly basic (e.g., pH equal to or greater than about 8), and the underlayer 154 can include SiN that is relatively easily etched by such a reaction solution. Also as described above, the reaction solution 170 (or other liquid or solution) may degrade the circuit 146 or otherwise render the circuit 146 inoperable or make the conductive and / or metallic portions of the circuit 146 less effective. For example, the reaction solution 170 can chemically react and oxidize the conductive and / or metallic portions of the circuit 146.

[0101] However, as Figure 8 shown, the protective layer 130 can be configured such that it forms a solid continuous barrier layer (without voids, cracks, or other discontinuities) that prevents any reaction solution 170 that penetrates the reaction structure 126 and potentially passes through the filter material 116 via the discontinuous portion 178 or otherwise penetrates the light guide 118 from interacting with the circuit 146 of the device 104. Additionally, the protective layer 130 can be configured such that it is chemically inert with respect to the reaction solution, such that when the reaction solution contacts the protective layer 130, the reaction solution (which, as described above, can include relatively high acidity or relatively high alkalinity) does not etch the protective layer 130 at about 100 degrees Celsius and about atmospheric pressure, or etches less than about one (1) angstrom of the thickness of the protective layer 130 per hour In this way, although there may be a discontinuous portion 178 or other path through the reaction structure 126 and / or a discontinuous portion 178 or other path through the filter material 116, the protective layer 130 prevents the reaction solution 170 from flowing to / through the discontinuous portion 179 of the underlayer 154 and ultimately interacting with the device circuit 146 (and thus degrading the device circuit 146). As described above, the method of formation, thickness, and material of the protective layer 130 can be configured independently or in consideration of each other such that the protective layer 130 has no discontinuities that would allow any solution or liquid (e.g., the reaction solution) to pass through the protective layer 130, and the protective layer 130 is chemically inert with respect to the reaction solution such that the protective layer 130 is resistant to (reaction solution) etching.

[0102] Figure 9-13illustrates an example of a method 200 of manufacturing an optical detection device such as Figure 1-8 the optical detection device 104 depicted. Thus, relative to "1", like reference numerals preceded by "2" are used to indicate like components, aspects, functions, processes, or operations, and the description thereof above applies equally and will not be repeated for purposes of brevity and clarity. For example, method 200 may adopt the structure or aspects of the various examples discussed herein (e.g., systems and / or methods). In various examples, certain steps may be omitted or added, certain steps may be combined, certain steps may be performed simultaneously, certain steps may be performed concurrently, certain steps may be divided into multiple steps, certain steps may be performed in a different order, or certain steps or sequences of steps may be re - executed in an iterative manner.

[0103] As Figure 9 and Figure 10 shown, the method 200 of forming device 204 may include forming (at 270 of Figure 9 ) a plurality of trenches 280 (e.g., an array) within device base 225. The plurality of trenches may extend from an outer / top surface of device base 225 and extend toward at least one corresponding optical sensor 240 (through the thickness of device base 225). As discussed above, device base 225 may include an array of optical sensors 240 and device circuitry 246 electrically coupled to optical sensors 240, the device circuitry 246 transmitting data signals based on photons detected by optical sensors 240. Device base 225 may be provided or obtained by any process. For example, method 200 may include obtaining device base 225 in a pre - assembled or pre - fabricated state, or may include forming or fabricating device base 225 prior to forming the plurality of trenches 280.

[0104] As discussed above, integrated circuit manufacturing techniques, such as CMOS manufacturing techniques, may be used to fabricate device base 225. For example, device base 225 may include a number of substrate layers (e.g., dielectric material layer 242) in which different modified features (e.g., metal elements) forming device circuitry 246 are embedded. The plurality of trenches 280 may be formed in a base layer (e.g., in dielectric material layer 242) to correspond to the portion of device base 225 that will include optical waveguides 218 after method 200. Although only one trench 280 is depicted in Figure 10 , device base 225 may include an array of optical waveguides 218 as described above, and thus an array of trenches 280 may be formed.

[0105] As Figure 10As shown, the trench 280 may pass through an opening in the first shielding layer 250 and / or the second shielding layer 252 and extend through the dielectric material 242 toward at least one corresponding photosensor 240. As Figure 10 As shown, the inner surface of the device base 225, such as its dielectric material 242, may define a trench 280 for forming an optical waveguide 218 therein. The trench 280 may extend to a second cushion layer 255 that extends through the dielectric material 242. Thus, the second cushion layer 255 may form the bottom of the trench 280. Also as Figure 10 As shown, other openings in the first shielding layer 250 and / or the second shielding layer 252 may be formed in the gap region 213 of the device base 225.

[0106] The trench 280 may be formed by any process or technique that removes portions of the dielectric material 242 (and potentially portions of the first shielding layer 250 and / or the second shielding layer 252). For example, the trench 280 may be formed by one or more selective etching processes or reactive ion etching processes. In one example, the trench 280 may be formed by applying at least one mask (not shown) to the device base 225 and removing (e.g., by etching) material from portions of the dielectric material 242 (and potentially removing portions of the first shielding layer 250 and / or the second shielding layer 252).

[0107] As Figure 9 and Figure 11 As shown, after forming a plurality of trenches 280, method 200 may include depositing (at 272 of Figure 9 ) a first cushion layer 254 above the top surface of the device base 225 and within the plurality of trenches 280. In some examples, the first cushion layer 254 may be formed above the sidewalls of the plurality of trenches 280 rather than above the second cushion layer 255 at the bottom of the trenches 280. In some other examples, the first cushion layer 254 may be formed above the second cushion layer 255 at the bottom of the trenches 280 but then removed. The first cushion layer 254 may be deposited above the second shielding layer 252 on the top surface of the device base 225 and potentially above any of the openings in the first shielding layer 250 and / or the second shielding layer 252 in the gap region 213 of the device base 225 such that the second shielding layer 252 extends over the dielectric material 242 in these openings, as Figure 11 As shown.

[0108] The first liner layer 254 can be formed by any process or technique. For example, the first liner layer 254 can be formed by at least one chemical deposition process (e.g., such as electroplating, chemical vapor deposition (CVD), plasma-enhanced CVD (PECVD), or atomic layer deposition (ALD)), physical deposition process, growth mode, epitaxial growth, or a combination thereof. In some examples, the first liner layer 254 can be conformally formed over the surface of the device pedestal 225 and within the trenches 280 (e.g., over the sidewalls of the trenches 280 and potentially over the bottom surface of the trenches 280). The first liner layer 254 can include a substantially constant thickness, or the thickness can vary. As discussed above, the first liner layer 254 (and / or potentially the second liner layer 255) can include (at the time of formation and / or after using the device 204) discontinuous portions that extend therethrough and permit a solution or liquid to flow therethrough (see Figure 8 ). Also as described above, the first liner layer 254 can chemically react with a reaction solution (which can be relatively highly acidic or basic / alkaline) such that the reaction solution etches through the first liner layer 254.

[0109] After the first liner layer 254 is formed on the device pedestal 225 (and within the trenches 280), the first liner layer 254 can be further processed. For example, at least a portion of the first liner layer 254 that extends over the top surface of the device pedestal 225 (i.e., the gap region 213 of the first liner layer 254) can be processed to be planarized / smoothed and / or otherwise improved in its surface topography. In some such examples, at least a portion of the first liner layer 254 that extends over the top surface of the device pedestal 225 (i.e., the gap region 213 of the first liner layer 254) can be etched and / or polished (e.g., chemically and / or mechanically polished / planarized) to planarize the outer surface of the first liner layer 254.

[0110] As Figure 9 and Figure 12 shown, method 200 can include depositing (at 274 of Figure 9 ) a protective layer 230 over the device pedestal 225 such that the protective layer 230 extends within the plurality of trenches 280. In some examples, method 200 can include depositing (at 274 of Figure 9 ) a protective layer 230 over the device pedestal 225 such that the protective layer 230 extends within the plurality of trenches 280 and extends over the top surface of the device pedestal 225. In some examples, the protective layer 230 can be formed over the sidewalls and the bottom of the plurality of trenches 280. The protective layer 230 can be formed over the first liner layer 254 and the second liner layer 255.

[0111] The protective layer 230 can be formed by any process or technique. For example, the protective layer 230 can be formed by at least one chemical deposition process (e.g., such as electroplating, chemical vapor deposition (CVD), plasma-enhanced CVD (PECVD), or atomic layer deposition (ALD)), physical deposition process, growth mode, epitaxial growth, or a combination thereof. In some examples, the protective layer 230 can be conformally formed over the surface of the device pedestal 225 and within the trenches 280 (e.g., over the sidewalls of the trenches 280 and potentially over the bottom surface of the trenches 280). The protective layer 230 can include a substantially constant thickness, or the thickness can vary. As discussed above, the protective layer 230 can be formed such that it has (at the time of formation and / or after using the device 204) no discontinuities extending therethrough and allowing a solution or liquid to flow therethrough (see Figure 8 ). The thickness, material, and / or formation process of the protective layer 230 can be configured such that the protective layer 230 is a liquid-impermeable barrier. For example, any process that forms the protective layer 230 as a robust, highly dense layer with a low defect density can be utilized. In some specific examples, the protective layer 230 is formed by, for example, an atomic layer deposition (ALD) process or a high-density plasma chemical vapor deposition (CVD) process. Thus, the protective layer 230 can be a liquid-impermeable barrier that prevents a liquid or solution, such as a reaction solution, from interacting with the device circuitry 246 in the device layer of the device pedestal 225.

[0112] Also as discussed above, the protective layer 230 can be formed such that it is chemically inert with respect to the reaction solution, such that when the reaction solution contacts the protective layer 230, the reaction solution (which, as described above, can include a relatively high acidity or a relatively high alkalinity) does not etch the protective layer 130 at about 100 degrees Celsius and about atmospheric pressure, or etches less than about one (1) angstrom of the thickness of the protective layer 130 per hour For example, the composition of the protective layer 230 can not chemically react with the composition of the reaction solution (which can include a relatively high acidity or a relatively high alkalinity), or only react to a relatively small extent, such that when the reaction solution contacts the protective layer 230, the reaction solution does not etch the protective layer 230 or etches less than about one (1) angstrom of the thickness of the protective layer 230 per hour at about 100 degrees Celsius and about atmospheric pressure Accordingly, the protective layer 230 may include an etch-resistant layer relative to the reaction solution (e.g., which may include a pH equal to or less than about 5 or a pH equal to or greater than about 8) to prevent the reaction solution from penetrating therein over time and ultimately interacting with the device circuitry 246, and corroding the device circuitry 246 or otherwise interfering with the function of the device circuitry 246. The protective layer 230 is thus formed to prevent a liquid or solution (e.g., the reaction solution) that may pass through the reaction structure 226 to reach the protective layer 230 or pass through the reaction structure 226 and the filter material 216 of the light guide 218 to reach the protective layer 230 from interacting with the device circuitry 246 (and the cushion layer 254 (if provided) and the dielectric material 242).

[0113] As Figure 9 and Figure 13 shown, after forming the protective layer 230, method 200 may include filling (at 276 of Figure 9 ) the plurality of cushioned trenches 280 with at least one filter material 216 to form a plurality of light guides 218. As discussed above, the at least one filter material 216 may filter light of a first wavelength (e.g., excitation light) and allow light of a second wavelength (e.g., light emitted from the reaction site) to pass through the filter material 216 to reach at least one corresponding light sensor 240. In some examples, the amount of the filter material 216 applied to the device base 225 may exceed the available volume within the cushioned trenches 280. Thus, the filter material 216 may overflow from the cushioned trenches 280 and extend along the top of the device base 225, e.g., above the first cushion layer 254. In an alternative example, the filling operation 276 may include selectively filling each cushioned trench 280 such that the filter material 216 does not clear / overflow the trenches 280 (i.e., extend above the top of the device base 225).

[0114] In some examples, filling (at 276 of Figure 9 ) the filter material 216 may include pressing the filter material 216 (e.g., using a squeegee component) into the cushioned trenches 280. Optionally, method 200 may further include removing the filter material 216 from the protective layer 230 and, in some cases, removing the portion of the filter material 216 within the light guides 218. The filter material 216 may be removed from within the light guides 218 such that the openings 258 of the light guides 218 are positioned at a depth below the protective layer 230, as Figure 13 shown. Different processes may be implemented to remove one or more portions of the filter material 216. For example, the removal operation may include at least one of etching a portion of the filter material 216 or chemically polishing a portion of the filter material 216.

[0115] Also as Figure 9 and Figure 13As shown, after forming the protective layer 230 on the device base 225 (and within the trench 280), the protective layer 230 can be further processed. For example, at least a portion of the protective layer 230 that extends above the top surface of the device base 225 (i.e., the gap region 213 of the protective layer 230) can be processed to be planarized / smoothed and / or otherwise improved in its surface topography. In some such examples, at least a portion of the protective layer 230 that extends above the top surface of the device base 225 (i.e., the gap region 213 of the protective layer 230) can be etched and / or polished (e.g., chemically and / or mechanically polished / planarized) to planarize the outer surface of the protective layer 230.

[0116] After forming the optical waveguides 218 through the filter material 216, method 200 can include forming (at 278 of Figure 9 ) a reaction structure above the plurality of optical waveguides 218 and above the protective layer 230 on the top surface of the device base 225 (see Figure 3 and Figure 4 ). As discussed above, the reaction structure disposed above the plurality of optical waveguides 218 and above the protective layer 230 on the top surface of the device base 225 can include a plurality of reaction grooves, each reaction groove corresponding to at least one optical waveguide, for containing at least one reaction site and a reaction solution. In some examples, a reaction solution having a pH less than or equal to about 5 or a pH greater than or equal to about 8 is provided on the reaction structure to form reaction sites on the reaction structure. After being treated with the reaction solution, the reaction sites can generate light emission in response to incident excitation light. For example, the reaction solution can initiate a reaction and / or form a reaction product at the reaction sites that generate light emission in response to the excitation light. Also as discussed above, the reaction structure can include multiple layers. Thus, forming (at 278 of Figure 9 ) the reaction structure can include forming multiple layers above the plurality of optical waveguides 218 and above the protective layer 230 on the top surface of the device base 225 (see Figure 3 and Figure 4 ). The reaction structure can be formed by any process or technique.

[0117] Accordingly, the protective layer 230 can form a support beneath the reaction structure. As discussed above, the planarized top surface of the protective layer 230 can thus minimize the surface topography modulation induced in the detector surface of the reaction structure, particularly in the gap region 213 of the detector surface. In a particular example, the treated protective layer 230 can result in a planar and / or smooth surface in the gap region 213 of the detector surface of the reaction structure and prevent reaction solutions or any other biological or chemical substances from remaining thereon and / or prevent jump errors. Compared to examples without the treated protective layer 230, the flatness of the gap region 213 of the detector surface provided at least in part by the treated underlying protective layer 230 can enhance the robustness of the detection device 204.

[0118] Optionally, method 200 may include providing at least one reaction site in at least one reaction recess of the formed reaction structure by introducing a reaction solution having a pH less than or equal to about 5 or a pH greater than or equal to about 8 above the reaction structure and / or mounting a flow cell on the device 204 (see Figure 1 ) that provides a reaction solution having a pH less than or equal to about 5 or a pH greater than or equal to about 8 above the reaction structure. Providing the reaction site can occur before or after the flow cell is coupled to the device 204. The reaction sites can be positioned in a predetermined pattern along the reaction recess. The reaction sites can correspond in a predetermined manner (e.g., one site corresponds to one light sensor, one site corresponds to multiple light sensors, or multiple sites correspond to one light sensor). In other examples, the reaction sites can be formed randomly along the reaction recess. As described herein, the reaction sites can include biological or chemical substances immobilized on the detector surface within the reaction recess. The biological or chemical substances can be configured to emit a light signal in response to excitation light. Accordingly, at least one reaction site can produce light emission only after being treated with the reaction solution in response to incident excitation light. For example, the reaction solution can initiate a reaction and / or form a reaction product at at least one reaction site that emits light in response to excitation light. In a particular instance, the reaction sites include clusters or colonies of biomolecules (e.g., oligonucleotides) immobilized on the detector surface within the reaction recess.

[0119] It is to be understood that the above description is intended to be illustrative and not restrictive. For example, the above examples (and / or aspects thereof) may be used in combination with each other. Additionally, many modifications may be made to adapt a particular situation or material to the teachings of various examples without departing from their scope. While the dimensions and types of materials may be described herein, they are intended to define parameters of some of the various examples and are in no way intended to be limiting to all examples, but rather are exemplary. Many other examples will be apparent to those of ordinary skill in the art upon review of the above description. Accordingly, the scope of the various examples should be determined with reference to the appended claims along with the full scope of equivalents to which those claims are entitled.

[0120] In the appended claims, the terms "including" and "in which" are used in their English original sense as equivalents to the corresponding terms "comprising" and "wherein". Additionally, in the appended claims, terms such as "first", "second", and "third", etc. are used only as reference labels and are not intended to impose numerical, structural, or other requirements on their objects. The forms of the term "based on" herein include relationships where an element is partially based on and relationships where an element is fully based on. The forms of the term "defining" include relationships where an element is partially defined and relationships where an element is fully defined. Further, the limitations of the appended claims are not written in means-plus-function form and are not intended to be interpreted under 35 U.S.C. § 112, ¶ 6, unless and until such claim limitations expressly use the phrase "means for" followed by a function recitation without further structure. It should be understood that not all of these objectives or advantages may be achieved in accordance with any particular example. Thus, for example, those skilled in the art will recognize that the apparatuses, systems, and methods described herein may be implemented or performed in a manner that achieves or optimizes one advantage or a group of advantages taught herein without necessarily achieving other objectives or advantages that may be taught or suggested herein.

[0121] Although the present disclosure has been described in detail in connection with only a limited number of examples, it should be readily understood that the present disclosure is not limited to these disclosed examples. Rather, the present disclosure may be modified to incorporate any number of variations, alterations, substitutions, or equivalent arrangements not heretofore described but commensurate with the spirit and scope of the present disclosure. Additionally, although various examples have been described, it should be understood that aspects of the present disclosure may include only one example or some of the described examples. Further, although some examples are described as having a certain number of elements, it should be understood that these examples may be practiced with fewer or greater than a certain number of elements.

[0122] It should be recognized that all combinations of the foregoing concepts and additional concepts discussed in more detail below, provided that such concepts are not mutually inconsistent, are considered to be part of the inventive subject matter disclosed herein. In particular, all combinations of the claimed subject matter appearing at the end of the present disclosure are considered to be part of the inventive subject matter disclosed herein.

Claims

1. A light detection device, comprising: A reaction structure that forms a plurality of reaction grooves and at least one reaction site, the at least one reaction site being located in the reaction grooves and generating light emission in response to incident excitation light after being treated with a reaction solution; And a device base positioned below the reaction structure, comprising: A plurality of light sensors; A device circuit electrically coupled to the light sensors to transmit data signals based on photons detected by the light sensors; A plurality of light guides having input regions that receive excitation light and light emission from at least one corresponding reaction groove of the reaction grooves, each light guide extending into the device base toward at least one corresponding light sensor, and the light guide comprising at least one filtering material that filters the excitation light and allows the light emission to be transmitted to the at least one corresponding light sensor; and A protective layer that extends around each light guide, wherein the protective layer abuts the plurality of light guides within the device base, the protective layer comprises a liquid-impermeable barrier layer, and the protective layer is chemically inert with respect to the reaction solution that passes above the reaction structure.

2. The device according to claim 1, further comprising a first shielding layer that extends between adjacent input regions to block the excitation light and light emission incident on the first shielding layer.

3. The device according to claim 1, wherein, The protective layer also extends between the top surface of the device base and a gap region of the reaction structure that extends around the reaction grooves.

4. The device according to claim 1, wherein, The protective layer comprises silicon dioxide, metal oxide, metal nitride, or a combination thereof.

5. The device according to claim 1, wherein The protective layer comprises silicon carbide, silicon oxycarbide, nitro silicon carbide, metal oxide, metal nitride, or a combination thereof.

6. The device according to claim 1, wherein, The pH of the reaction solution is greater than or equal to 8.

7. The apparatus according to claim 6, wherein, The protective layer comprises silicon dioxide, silicon oxynitride, silicon monoxide, silicon carbide, silicon oxycarbide, nitro silicon carbide, metal oxide, metal nitride, or a combination thereof.

8. The device according to claim 1, wherein The pH of the reaction solution is less than or equal to 5.

9. The device according to claim 8, wherein, The protective layer comprises silicon carbide, silicon oxycarbide, nitro silicon carbide, metal oxide, metal nitride, or a combination thereof.

10. The apparatus according to claim 1, wherein, The device circuit comprises interconnected conductive elements, and the protective layer prevents the reaction solution from oxidizing the conductive elements.

11. The device according to claim 1, wherein, The thickness of the protective layer is in the range of 5 nanometers to 100 nanometers.

12. The apparatus according to claim 1, wherein, The reaction structure comprises at least one reaction site fixed within each of the reaction grooves.

13. The device according to claim 12, wherein, The at least one reaction site comprises at least one analyte, and wherein the reaction solution comprises at least one fluorescently labeled molecule.

14. The apparatus according to claim 1, wherein, The device circuit of the device base forms a complementary metal oxide semiconductor (CMOS) circuit.

15. A biosensor, comprising: The device according to claim 1; And A flow cell, the flow cell being mounted on the device, the flow cell including the reaction solution and at least one flow channel, the at least one flow channel being in fluid communication with the plurality of reaction grooves of the reaction structure to direct the reaction solution to the plurality of reaction grooves.

16. A method of using the optical detection device of claim 1, comprising: Passing the reaction solution having a pH less than or equal to 5 or a pH greater than or equal to 8 over the reaction structure of the optical detection device.

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