Biowafer

Abstract

The invention discloses a biochip. The biochip comprises a substrate and a waveguide core layer, and the waveguide core layer is arranged above the substrate. The waveguide core layer includes a first grating coupler. The biochip also includes a hydrogel that is cross-linked via hydrogel cross-linking light, the hydrogel cross-linking light being coupled by a first grating coupler.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to a biochip, and in particular, to a biochip comprising a waveguide-assisted hydrogel cross-linking technique for selective immobilization and multiplexed detection of biological samples. BACKGROUND

[0002] Integrated sensing devices have recently become popular tools for bioanalysis. In such applications, biological or biochemical samples can be placed on a biochip. Biological reactions or interactions (e.g., DNA sequencing and immunofluorescence detection) can be presented by their results through excitation or emission spectra, or through the intensity of fluorescent molecules. Fluorescent molecules can be excited by excitation light with a shorter wavelength and generate emission light with a longer wavelength toward a photoelectric conversion element (e.g., a photodetector). The photoelectric conversion element can detect and measure the spectral distribution and intensity of fluorescence.

[0003] While existing biochips are generally adequate for their intended purposes, they are not entirely satisfactory in all respects. Therefore, there still remains a need for a novel biochip. SUMMARY

[0004] The present disclosure aims to provide a biochip to solve at least one of the above problems.

[0005] In an embodiment of the present disclosure, a biochip comprising a waveguide core layer is provided. The waveguide core layer comprises at least one grating coupler for coupling light to cross-link a hydrogel to improve the selective modification and / or multiplexed screening capability of the biochip by thin layer hydrogel.

[0006] An embodiment of the present disclosure provides a biochip. The biochip comprises a substrate and a waveguide core layer disposed above the substrate. The waveguide core layer comprises a first grating coupler. The biochip also comprises a hydrogel cross-linked by a hydrogel cross-linking light coupled through the first grating coupler.

[0007] In some embodiments, the substrate has a photoelectric conversion element, and the hydrogel corresponds to the photoelectric conversion element.

[0008] In some embodiments, the biochip further comprises an upper cladding layer disposed on the waveguide core layer. The upper cladding layer comprises a nanopore disposed above the photoelectric conversion element, the upper cladding layer exposes the first grating coupler, and the hydrogel is disposed at a bottom of the nanopore.

[0009] In some embodiments, the thickness of the upper cladding layer is greater than 50 nanometers.

[0010] In some embodiments, the distance between the uppermost layer of the hydrogel and the waveguide core layer is less than 100 nanometers when the thickness of the upper cladding layer is greater than 100 nanometers.

[0011] In some embodiments, the substrate has a plurality of photoelectric conversion elements, and the upper cladding layer includes a plurality of nanopores disposed above the photoelectric conversion elements, and a plurality of hydrogels are disposed at the bottom of the nanopores.

[0012] In some embodiments, the biochip further includes a self-assembled monolayer disposed on the upper cladding layer and between the upper cladding layer and the hydrogel.

[0013] In some embodiments, the first grating coupler is used to couple a hydrogel cross-linking light and a sensing light, and the wavelength of the hydrogel cross-linking light is shorter than the wavelength of the sensing light.

[0014] In some embodiments, the first grating coupler is used to couple a hydrogel cross-linking light, and the waveguide core layer further includes a second grating coupler disposed on the other side of the first grating coupler. The second grating coupler is used to couple a sensing light, and the wavelength of the hydrogel cross-linking light is shorter than the wavelength of the sensing light.

[0015] In some embodiments, the biochip further includes a lower cladding layer disposed between the substrate and the waveguide core layer.

[0016] In some embodiments, the waveguide core layer is formed as a channel waveguide, and the channel waveguide includes at least a first grating coupler disposed above one side of the substrate, a second grating coupler disposed above the other side of the substrate, and a plurality of channels connecting the first grating coupler and the second grating coupler.

[0017] In some embodiments, there are a plurality of staggered first grating couplers.

[0018] In some embodiments, the channel waveguide further includes a light splitting element connecting the second grating coupler and the channels.

[0019] In some embodiments, the first grating couplers are arranged in an array.

[0020] In some embodiments, the hydrogel is disposed on all channels, and the hydrogels on different channels have different functional molecules or concentrations.

[0021] In some embodiments, at least one first grating coupler is used to couple light of the same or shorter wavelength as the light coupled through the second grating coupler.

[0022] In some embodiments, the hydrogel is disposed on one channel to form a sensing arm, and other channels without hydrogel form a reference arm.

[0023] In some embodiments, the hydrogel comprises gelatin methacrylate (GelMA), polyethylene glycol diacrylate (PEGDA), or hyaluronic acid (HA).

[0024] In some embodiments, the hydrogel comprises a plurality of functional molecules, and the functional molecules comprise DNA primers, a concanavalin A-dextran FRET complex, or an antibody.

[0025] In some embodiments, the biochip further comprises a microneedle structure connecting the hydrogel and an external component. BRIEF DESCRIPTION OF DRAWINGS

[0026] The embodiments of the present disclosure will be described in detail with reference to the attached drawings. It should be noted that the various features are not drawn to scale, according to standard practice in the industry. In fact, the dimensions of the various features can be exaggerated or reduced for the sake of clarity in illustrating the technical features of the embodiments of the present disclosure.

[0027] Figures 1A-1J is a perspective schematic view showing various stages of a method of manufacturing a biochip according to some embodiments of the present disclosure.

[0028] Figure 2 is a cross-sectional view showing a portion of a biochip.

[0029] Figure 3 is a (magnified) schematic view showing a hydrogel and functional molecules inside.

[0030] Figure 4 is a perspective schematic view showing a biochip according to some embodiments of the present disclosure.

[0031] Figure 5 is a perspective schematic view showing a biochip according to some other embodiments of the present disclosure.

[0032] Figures 6A-6O is a perspective schematic view showing various stages of a method of manufacturing a biochip according to some embodiments of the present disclosure.

[0033] Figure 7 is a perspective schematic view showing a biochip according to some embodiments of the present disclosure.

[0034] Figures 8A-8E is a perspective schematic view showing various stages of a method of manufacturing a biochip according to some embodiments of the present disclosure.

[0035] Figure 9 is a perspective schematic view showing a biochip according to some embodiments of the present disclosure.

[0036] Figure 10A schematic diagram showing the effect of glucose on functional molecules in the hydrogel of the biochip.

[0037] Figure 11 A glucose response spectrum is shown.

[0038] Figure 12 A biochip is shown applied to the skin of a living body according to some embodiments of the present disclosure.

[0039] Reference signs are as follows:

[0040] 100, 100', 102, 104, 106: biochip

[0041] 10: substrate

[0042] 12: photoelectric conversion element

[0043] 20: lower cladding layer

[0044] 300: waveguide material layer

[0045] 30: waveguide core layer

[0046] 30', 30": channel waveguide

[0047] 31, 32, 33, 34, 35, 36: grating coupler

[0048] 31L, 32L, 33L, 34L, 35L: channel

[0049] 36LS: light splitting element

[0050] 40: upper cladding layer

[0051] 40W: nanopore

[0052] 50: self-assembled monolayer

[0053] 60: hydrogel precursor

[0054] 60-1, 60-2, 60-3, 60-4, 60-5: hydrogel precursor

[0055] 61, 62, 63, 64, 65: hydrogel

[0056] 62f: functional molecule

[0057] 69: microneedle structure

[0058] B1, B2, B3: sample

[0059] CA1: concanavalin A

[0060] D1, D2: distribution map

[0061] DG: dextran

[0062] HM: hidden mask

[0063] L1: hydrogel cross-linking light

[0064] L2: sensing light

[0065] MN: microneedle

[0066] S1, S2: light source

[0067] SK: skin

[0068] UV: hydrogel cross-linking light

[0069] λ1, λ2, λ3: wavelength DETAILED DESCRIPTION

[0070] The following disclosure provides many different embodiments, or examples, for implementing different features of the application. Specific examples of components and arrangements are described below to simplify the present disclosure. These are, of course, merely examples and are not intended to be limiting. For example, the specification can describe a particular feature as being implemented in one embodiment, but this does not mean that the feature is not implemented in other embodiments. In addition, it should be appreciated that components can be added or removed from one or more embodiments with equal advantage.

[0071] It should be understood that other operations can be implemented before, between, or after the described operations and that some operations can be substituted or omitted in other embodiments of the method.

[0072] Furthermore, spatially relative terms, such as "beneath", "below", "lower", "above", "upper", and the like, can be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. The spatially relative terms can encompass different orientations of the device in use or operation, including the various orientations of the device described herein. The apparatus can be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly.

[0073] In the present disclosure, the terms "about," "approximately," "substantially" generally mean within 20% of a given value, or within 10% of a given value, or within 5% of a given value, or within 3% of a given value, or within 2% of a given value, or within 1% of a given value, or even within 0.5% of a given value. A given value of the present disclosure is about the value. That is, a given value can include "about," "approximately," "substantially" unless specifically described otherwise.

[0074] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined in the embodiments of the present disclosure.

[0075] The present disclosure can make use of the same reference numbers and / or letters in the following embodiments. These repetitions are for the purpose of simplification and clarity, and are not intended to define a specific relationship between the various embodiments and / or structures being discussed.

[0076] Figures 1A-1J are shown in perspective schematic views of various stages of a method of manufacturing a biological wafer 100 according to some embodiments of the present disclosure. It should be noted that, for the sake of brevity, Figures 1A-1J Some components have been omitted in

[0077] Referring to Figure 1A In some embodiments, a substrate 10 having a photoelectric conversion element 12 is provided. In some embodiments, the substrate 10 can be a glass substrate or a semiconductor substrate (e.g., a CMOS substrate), and the photoelectric conversion element 12 can be a photodiode. For example, the substrate 10 can include a flexible material such as polyethylene terephthalate (PET), polyethersulfone (PES), polyimide (PI), polycarbonate (PC), polymethyl methacrylate (PMMA), silicone, epoxy, the like, or a combination thereof. The substrate 10 can also include a rigid material such as glass, quartz, or sapphire.

[0078] The substrate 10 can be transparent or translucent. More specifically, in the case where the substrate 10 is transparent, the material of the substrate 10 has a transmittance of greater than about 85%, or greater than about 92%, for light having a wavelength ranging from 400 nanometers (nm) to 750 nm. In the case where the substrate 10 is translucent, the material of the substrate 10 has a transmittance of greater than about 25% and less than about 85% for light having a wavelength ranging from 400 nm to 750 nm, although embodiments of the present disclosure are not limited thereto.

[0079] Referring to Figure 1B In some embodiments, a lower cladding layer 20 is formed on the substrate 10. For example, the lower cladding layer 20 can include a transparent dielectric material having a low refractive index between about 1.0 to about 1.99, such as silicon dioxide (SiO2), although embodiments of the present disclosure are not limited thereto. The lower cladding layer 20 can be formed by a deposition process, such as chemical vapor deposition (CVD), plasma-enhanced chemical vapor deposition (PECVD), atomic layer deposition (ALD), other similar processes, or a combination thereof, although embodiments of the present disclosure are not limited thereto. It should be noted that the lower cladding layer 20 can be omitted in embodiments where the substrate 10 is a glass substrate.

[0080] Referring to Figure 1C In some embodiments, a waveguide core layer 30 is formed on the substrate 10. In other words, the lower cladding layer 20 is disposed between the substrate 10 and the waveguide core layer 30. For example, the waveguide core layer 30 can include silicon nitride (SiN), tantalum oxide (TaO), titanium dioxide (TiO), aluminum oxide (AlO), other similar materials, or a combination thereof, although embodiments of the present disclosure are not limited thereto. The waveguide core layer 30 can be formed by a deposition process. Examples of the deposition process have been described previously and will not be repeated here.

[0081] Referring to Figure 1D In some embodiments, a grating coupler 31 is formed on one side of the waveguide core layer 30. The grating coupler 31 can be formed by a photolithography process and / or an etching process. For example, the photolithography process can include resist coating (e.g., spin coating), soft bake, mask alignment, exposure, post-exposure bake (PEB), development, rinse, dry (e.g., hard bake), other suitable processes, or a combination thereof, although embodiments of the present disclosure are not limited thereto.

[0082] Referring to Figure 1E In some embodiments, an upper cladding layer 40 is formed on the waveguide core layer 30. As shown in FIG. 1C, the upper cladding layer 40 exposes the grating coupler 31. The upper cladding layer 40 can include the same or similar material as the lower cladding layer 20 and can be formed by the same or similar process, which will not be repeated here. Figure 1E

[0083] Referring to Figure 1F In some embodiments, the upper cladding layer 40 is patterned to form a nano- aperture (vial) 40W. As shown in FIG. 1D, the nano-aperture 40W is disposed above (or corresponding to) the optoelectronic conversion element 12. In some embodiments, the nano-aperture 40W is proximate to but does not penetrate the upper cladding layer 40. That is, there is a gap between the bottommost portion of the nano-aperture 40W and the waveguide core layer 30. Figure 1F ​​

[0084] The nanopores 40W can be formed by a patterning process. The patterning process can include, for example, forming a mask layer (not shown) on the upper cladding layer 40, and then etching portions of the upper cladding layer 40 not covered by the mask layer, although embodiments of the present disclosure are not limited thereto.

[0085] The mask layer can include a photoresist, such as a positive photoresist or a negative photoresist. For example, the mask layer can include a metal, a metal oxide, a metal nitride (e.g., titanium, titanium dioxide, titanium nitride, aluminum, aluminum oxide, aluminum nitride, chromium, or niobium), or a dielectric material (e.g., silicon oxide (SiO2), silicon nitride (SiN), silicon oxynitride (SiON), silicon carbide (SiC), silicon carbonitride (SiCN)), or a combination thereof. The mask layer can be a single layer structure or a multi-layer structure.

[0086] Referring to Figure 1G In some embodiments, a self-assembled monolayer (SAM) 50 is formed on the upper cladding layer 40. More specifically, the self-assembled monolayer 50 is formed on the top surface of the upper cladding layer 40 and within the nanopores 40W (i.e., on the bottom and sidewalls of the upper cladding layer 40). For example, the self-assembled monolayer 50 can include a silicon hydride (silane), although embodiments of the present disclosure are not limited thereto. The self-assembled monolayer 50 can be formed by a deposition process, such as a spin coating or vapor deposition process.

[0087] Referring to Figure 1H In some embodiments, a hydrogel prepolymer 60 is formed on the self-assembled monolayer 50. In the present embodiment, the hydrogel prepolymer 60 is formed in the nanopores 40W of the upper cladding layer 40. Further, the hydrogel prepolymer 60 can completely fill the nanopores 40W of the upper cladding layer 40, although embodiments of the present disclosure are not limited thereto. Here, the hydrogel prepolymer 60 has not yet been crosslinked and can be formed by a deposition process.

[0088] Referring to Figure 1I In some embodiments, the hydrogel crosslinking light L1 is coupled by the grating coupler 31 to form the (crosslinked) hydrogel 62 corresponding to the photoelectric conversion element 12. More specifically, the light source S1 emits light to the grating coupler 31 of the waveguide core layer 30, and forms the hydrogel crosslinking light L1 having a wavelength of λ1, and passes through the waveguide core layer 30. Since the nanopores 40W are close to the waveguide core layer 30, portions of the hydrogel prepolymer 60 in the bottom of the nanopores 40W are crosslinked by the hydrogel crosslinking light L1 coupled by the grating coupler 31 to form the hydrogel 62. That is, in some embodiments, the hydrogel 62 is disposed at the bottom of the nanopores 40W.

[0089] Here, the uncrosslinked hydrogel precursor 60 can have a photo-initiator including a UV photo-initiator (e.g., Irgacure 2959) or a visible light initiator (e.g., Eosin Y or Lithium phenyl-2,4,6-trimethylbenzoylphosphinate, LAP), and the hydrogel crosslinking light L1 can have a wavelength in the photosensitive region of the photo-initiator. In some embodiments, the hydrogel 62 includes gelatin methacrylate (GelMA), polyethylene glycol diacrylate (PEGDA), or hyaluronic acid (HA).

[0090] Referring to Figure 1J In some embodiments, another portion of the hydrogel precursor 60 that is not crosslinked by the hydrogel crosslinking light L1 is removed to form the biochip 100. In other words, the uncrosslinked hydrogel precursor 60 is washed away, thereby exposing the self-assembled monolayer 50 and the hydrogel 62.

[0091] Figure 2 A cross-sectional view showing a portion of the biochip 100. In more detail, Figure 2 The waveguide core layer 30, the upper cladding layer 40, the self-assembled monolayer 50, and the hydrogel 62 are shown. As Figure 1J As shown in FIG. 1A, the biochip 100 includes a waveguide core layer 30, an upper cladding layer 40, a self-assembled monolayer 50, and a hydrogel 62. Figure 2 In this embodiment, the self-assembled monolayer 50 is disposed on the upper cladding layer 40 and between the upper cladding layer 40 and the hydrogel 62. In more detail, the self-assembled monolayer 50 is disposed on the top surface of the upper cladding layer 40 and on the bottom and sidewalls of the nanohole 40W.

[0092] As shown in FIG. 1A, the biochip 100 includes a waveguide core layer 30, an upper cladding layer 40, a self-assembled monolayer 50, and a hydrogel 62. Figure 2 In some embodiments, the thickness T40 of the upper cladding layer 40 is greater than about 50 nanometers, which can isolate the hydrogel precursor 60 from being crosslinked at the evanescent wave region (i.e., the transmission path of the hydrogel crosslinking light L1) of the waveguide core layer 30. As Figure 2 As shown in FIG. 1A, the biochip 100 includes a waveguide core layer 30, an upper cladding layer 40, a self-assembled monolayer 50, and a hydrogel 62. In some embodiments, when the thickness T40 of the upper cladding layer 40 is greater than about 100 nanometers, the distance P between the uppermost layer of the hydrogel 62 and the waveguide core layer 30 is less than about 100 nanometers, which can be less than the penetration depth (e.g., about 30-50 nanometers) of the wavelength λ1, and thus the portion of the hydrogel precursor 60 at the bottom of the nanohole 40W can be crosslinked by the hydrogel crosslinking light L1. In addition, the top surface of the hydrogel 62 can become a binding region for a biological sample.

[0093] Figure 3 A (magnified) schematic diagram showing the hydrogel 62 and the functional molecules 62f inside. As shown, in some embodiments, the hydrogel 62 contains a plurality of functional molecules 62f, which can bind with analytes with fluorescent tags. In addition, in some embodiments, the functional molecules 62f contain DNA primers, Concanavalin A (Con A)-Dextran FRET complex, or antibodies. For example, the DNA primers can immobilize DNA fragments for DNA hybridization or DNA sequencing, the Concanavalin A (Con A)-Dextran FRET complex can detect glucose molecules, and the antibodies can bind with specific antigens or analytes from neighboring cells for screening cell phenotypes. Figure 3

[0094] Figure 4 is a perspective schematic diagram showing a biochip 100 according to some embodiments of the present disclosure. It should be noted that, for brevity, Figure 4 some components of the biochip 100 have been omitted. As shown, in some embodiments, the biochip 100 contains a substrate 10 and a waveguide core layer 30 disposed above the substrate 10. The substrate 10 has a photoelectric conversion element 12. The biochip 100 also contains a hydrogel 62 corresponding to the photoelectric conversion element 12. The waveguide core layer 30 contains a grating coupler 31. The hydrogel 62 is cross-linked by a hydrogel cross-linking light (L1 shown in FIG. 1I), which is coupled through the first grating coupler 31. Figure 4

[0095] In the present embodiment, the biochip 100 further contains a lower cladding layer 20 and an upper cladding layer 40. The lower cladding layer 20 is disposed between the substrate 10 and the waveguide core layer 30, while the upper cladding layer 40 is disposed on the waveguide core layer 30. The upper cladding layer 40 contains a nanopore 40W, which is disposed above the photoelectric conversion element 12. The upper cladding layer 40 exposes the grating coupler 31, and the hydrogel 62 is disposed at the bottom of the nanopore 40W. In addition, the biochip 100 contains a self-assembled monolayer 50, which is disposed on the upper cladding layer 40 and between the upper cladding layer 40 and the hydrogel 62.

[0096] As shown, in some embodiments, the substrate 10 has a plurality of photoelectric conversion elements 12, and the upper cladding layer contains a plurality of nanopores 40W, which are disposed above the plurality of photoelectric conversion elements 12, and there are a plurality of hydrogels 62 disposed at the bottom of the plurality of nanopores 40W. Figure 4

[0097] ​​​In this embodiment, the grating coupler 31 is used to couple the hydrogel crosslinking light L1 (see Figure 1I) and the sensing light L2, and the wavelength λ1 of the hydrogel crosslinking light L1 is shorter than the wavelength λ2 of the sensing light L2. Figure 4 As shown, light source S2 emits light towards the grating coupler 31 of the waveguide core layer 30, forming a sensing light L2 with wavelength λ2 that passes through the waveguide core layer 30. The sensing light L2 with wavelength λ2 can excite fluorescent molecules to emit fluorescence, which can be collected by the photoelectric conversion element 12 (e.g., a photodiode) below the nanopore 40W. In other words, the hydrogel crosslinked light L1 (with wavelength λ1) and the sensing light L2 (with wavelength λ2) can be coupled into the waveguide core layer 30 through the same grating coupler 31. That is, the grating coupler 31 can simultaneously perform optical coupling of λ1 and λ2, and the optical coupling angles can be different (since λ1≤λ2), but this embodiment is not limited thereto.

[0098] Figure 5 This is a three-dimensional schematic diagram illustrating a biochip 100' according to some other embodiments of this disclosure. Similarly, for the sake of brevity, Figure 5 Some components of the 100' biochip have been omitted. For example... Figure 5 As shown, in some embodiments, the biochip 100 includes a grating coupler 31 for coupling the hydrogel crosslinking light L1 (see Figure 1). Figure 1I The waveguide core layer 30 further includes a grating coupler 36, which is disposed on the other side of the grating coupler 31. The grating coupler 36 is used to couple the sensing light L2, and the wavelength λ1 of the hydrogel crosslinked light L1 is shorter than the wavelength λ2 of the sensing light L2.

[0099] In other words, in this embodiment, the hydrogel crosslinked light L1 and the sensing light L2 can be designed to be coupled and guided by different grating couplers (e.g., grating coupler 31 and grating coupler 36), and set to the same grating depth. The period and fill factor of the different grating coupler designs can be optimized for different light sources (e.g., light source S1 and light source S2) to match the required coupling angle and incident light wavelength.

[0100] Figures 6A-6O This is a three-dimensional schematic diagram illustrating various stages of a method for manufacturing a biochip 102 according to some embodiments of this disclosure. It should be noted that, for the sake of brevity, Figures 6A-6O Some components have been omitted.

[0101] Reference Figure 6A In some embodiments, a substrate 10 is provided. It should be noted that the substrate 10 may also have multiple photoelectric conversion elements (not shown in the original text). Figures 6A-6O (As shown in the image). Reference Figure 6BIn some embodiments, the lower cladding layer 20 and the waveguide material layer 300 are formed on the substrate 10 in sequence. Similarly, the lower cladding layer 20 can be omitted in embodiments where the substrate 10 is a glass substrate.

[0102] Referring to Figure 6C In some embodiments, grating couplers 31, 32, 33, 34, and 35 are formed on one side of the waveguide material layer 300 (over the one side of the substrate 10), and grating coupler 36 is formed on the other side of the waveguide material layer 300 (over the other side of the substrate 10). The grating couplers 31, 32, 33, 34, 35 and the grating coupler 36 can be formed by a photolithography process and / or an etching process.

[0103] Referring to Figure 6D With Figure 6E In some embodiments, the waveguide material layer 300 is patterned to form the channel waveguide 30'. In more detail, an interlaced mask layer HM can be formed on the waveguide material layer 300, and then the portions of the waveguide material layer 300 not covered by the mask layer HM are removed to form the channel waveguide 30'. In other words, the waveguide material layer 300 not covered by the mask layer HM can be etched, thereby leaving the channel waveguide 30'.

[0104] As shown in Figure 6E In some embodiments, the channel waveguide 30' includes the grating couplers 31, 32, 33, 34, and 35 over the one side (e.g., the right side in Figure 6E ), the grating coupler 36 over the other side (e.g., the left side in Figure 6E ), and the plurality of channels 31L, 32L, 33L, 34L, and 35L connecting the grating couplers 31, 32, 33, 34, and 35 to the grating coupler 36, respectively. In this embodiment, the grating couplers 31, 32, 33, 34, and 35 are interlaced grating couplers, and thus the grating couplers 31, 32, 33, 34, and 35 can be more densely arranged. As shown in Figure 6E In some embodiments, the grating couplers 31, 32, 33, 34, and 35 are arranged in an array.

[0105] It should be noted that the number of the grating couplers 31, 32, 33, 34, and 35 (which are over the right side of the substrate 10 in Figure 6E ) is not limited to five, and can be adjusted according to actual needs. In addition, in some embodiments, the channel waveguide 30' further includes a light splitting element 36LS connecting the grating coupler 36 to the channels 31L, 32L, 33L, 34L, and 35L.

[0106] Referring to Figure 6FIn some embodiments, a (droplet-like) hydrogel precursor 60-1 is formed on the channel waveguide 30' and is in contact with at least the channel 31L. Then, the light source S1 emits hydrogel crosslinking light at a wavelength of λ1 (not in the light source). Figure 6F (The light, marked in the middle), enters the grating coupler 31, and the hydrogel-crosslinked light passes through channel 31L. (See reference...) Figure 6G In some embodiments, a cross-linked hydrogel 61 is formed on channel 31L. Since the hydrogel cross-linking light only passes through channel 31L, the portion of the hydrogel precursor 60-1 located on channel 31L can be cross-linked by the hydrogel cross-linking light, while the other uncross-linked portions of the hydrogel precursor 60-1 can be removed (e.g., washed away).

[0107] Reference Figure 6H In some embodiments, a (droplet-like) hydrogel precursor 60-2 is formed on the channel waveguide 30' and is in contact with at least the channel 32L. Then, the light source S1 emits hydrogel crosslinking light at a wavelength of λ1 (not in the light source). Figure 6H (The light, marked in the middle), enters the grating coupler 32, and the hydrogel-crosslinked light passes through channel 32L. (See reference...) Figure 6I In some embodiments, a cross-linked hydrogel 62 is formed on channel 32L. Since the hydrogel cross-linking light only passes through channel 32L, the portion of the hydrogel precursor 60-2 located on channel 32L can be cross-linked by the hydrogel cross-linking light, while the other uncross-linked portions of the hydrogel precursor 60-2 can be removed (e.g., washed away).

[0108] Reference Figure 6J In some embodiments, a (droplet-like) hydrogel precursor 60-3 is formed on the channel waveguide 30' and is in contact with at least the channel 33L. Then, the light source S1 emits hydrogel crosslinking light at a wavelength of λ1 (not in the light source). Figure 6J (The light, marked in the middle), enters the grating coupler 33, and the hydrogel-crosslinked light passes through channel 33L. (See reference...) Figure 6K In some embodiments, a cross-linked hydrogel 63 is formed on channel 33L. Since the hydrogel cross-linking light only passes through channel 33L, the portion of the hydrogel precursor 60-3 located on channel 33L can be cross-linked by the hydrogel cross-linking light, while the other uncross-linked portions of the hydrogel precursor 60-3 can be removed (e.g., washed away).

[0109] Reference Figure 6L In some embodiments, a (droplet-like) hydrogel precursor 60-4 is formed on the channel waveguide 30' and is in contact with at least the channel 34L. Then, the light source S1 emits hydrogel crosslinking light at a wavelength of λ1 (not in the light source). Figure 6L (The light, marked in the middle), enters the grating coupler 34, and the hydrogel-crosslinked light passes through channel 34L. (See reference...) Figure 6MIn some embodiments, a cross-linked hydrogel 64 is formed on the channel 34L. Since the hydrogel cross-linking light only passes through the channel 34L, the portion of the hydrogel precursor 60-4 located on the channel 34L can be cross-linked by the hydrogel cross-linking light, while the other portion of the hydrogel precursor 60-4 that is not cross-linked can be removed (e.g., washed away).

[0110] Referring to Figure 6N In some embodiments, a (droplet-like) hydrogel precursor 60-5 is formed on the channel waveguide 30' and at least in contact with the channel 35L. Then, the light source S1 emits a hydrogel cross-linking light with a wavelength λ1 (not labeled in Figure 6N ) into the grating coupler 35, and the hydrogel cross-linking light passes through the channel 35L. Referring to Figure 6O In some embodiments, a cross-linked hydrogel 65 is formed on the channel 35L. Since the hydrogel cross-linking light only passes through the channel 35L, the portion of the hydrogel precursor 60-5 located on the channel 35L can be cross-linked by the hydrogel cross-linking light, while the other portion of the hydrogel precursor 60-5 that is not cross-linked can be removed (e.g., washed away).

[0111] As shown in Figures 6F-6O , in some embodiments, the hydrogels (e.g., 61, 62, 63, 64, and 65) are disposed on all channels (e.g., 31L, 32L, 33L, 34L, and 35L), and the hydrogels on different channels have different functional molecules or concentrations. More specifically, the hydrogel precursors 60-1, 60-2, 60-3, 60-4, and 60-5 can have different functional molecules or concentrations. Thus, in the present embodiments, the hydrogels 61, 62, 63, 64, and 65 are disposed on the channels 31L, 32L, 33L, 34L, and 35L, respectively, and the hydrogels 61, 62, 63, 64, and 65 have different functional molecules or concentrations.

[0112] Figure 7 is a perspective view showing a biochip 102 according to some embodiments of the present disclosure. It should be noted that, for the sake of brevity, Figure 7 some components of the biochip 102 have been omitted. As shown in Figure 7 In some embodiments, the light source S2 emits light to the grating coupler 36 of the channel waveguide 30', and sensing light with a wavelength λ2 is separated by the light splitting element 36LS and passes through the channels 31L, 32L, 33L, 34L, and 35L. In the present embodiments, the grating couplers 31, 32, 33, 34, and 35 are used to couple light with the same or shorter wavelength as the light coupled by the grating coupler 36.

[0113] Hydrogels 61, 62, 63, 64, and 65, containing different functional molecules (or different concentrations), can bind fluorescently tagged analytes at channels 31L, 32L, 33L, 34L, and 35L. After loading and washing a biological sample, the specific analyte with the fluorescent tag can be immobilized on the hydrogel. Then, by coupling sensing light with wavelength λ2 to channel waveguide 30', the sensing light can propagate in channel waveguide 30' and be separated into individual channels to excite fluorescent molecules and emit fluorescent signals. If a specific analyte is present in the biological sample (e.g., samples B1, B2, and B3), the hydrogel on the corresponding channel (e.g., channels 32L, 34L, and 35L) will emit a designed fluorescent signal, which can be collected by an objective lens or a photoelectric conversion element (e.g., a photodiode).

[0114] Figures 8A-8E This is a three-dimensional schematic diagram illustrating various stages of a method for manufacturing a biochip 104 according to some embodiments of the present disclosure. It should be noted that, for the sake of brevity, Figures 8A-8E Some components have been omitted. Furthermore, Figure 8A Possibly continuing Figure 6B The stages shown are not limited to those described herein.

[0115] Reference Figure 8A In some embodiments, a grating coupler 31 is formed on one side of the waveguide material layer 300 (located above the left side of the substrate 10), and a grating coupler 36 is formed on the other side of the waveguide material layer 300 (located above the right side of the substrate 10). The grating coupler 31 and the grating coupler 36 can be formed by photolithography and / or etching processes.

[0116] Reference Figure 8B and Figure 8C In some embodiments, the waveguide material layer 300 is patterned to form the channel waveguide 30. More specifically, a masking layer HM may be formed on the waveguide material layer 300, and then the portion of the waveguide material layer 300 not covered by the masking layer HM is removed to form the channel waveguide 30. In other words, the portion of the waveguide material layer 300 not covered by the masking layer HM may be etched to preserve the channel waveguide 30.

[0117] like Figure 8C As shown, in some embodiments, the channel waveguide 30” includes a portion disposed on one side of the substrate 10 (e.g., Figure 8C The grating coupler 31, located on the left side of the substrate 10, is disposed on the other side of the substrate 10 (e.g., on the left side). Figure 8C The grating coupler 36 on the right side of the image and the multiple channels 31L, 32L that connect the grating coupler 31 to the grating coupler 36.

[0118] Reference Figure 8DIn some embodiments, the (liquid droplet-like) hydrogel precursor 60 is formed on the channel 31L. Next, the light source S1 emits the hydrogel cross-linking light (not labeled in the figure) with a wavelength of λ1 into the grating coupler 31, and the hydrogel cross-linking light passes through the channel 31L. Referring to Figure 8D , in some embodiments, the (cross-linked) hydrogel 62 is formed on the channel 31L. Since the hydrogel precursor 60 is formed on the channel 31L but not on the channel 32L, the portion of the hydrogel precursor 60 on the channel 31L is cross-linked by the hydrogel cross-linking light, and the other portion of the hydrogel precursor 60 that is not cross-linked can be removed (e.g., washed away). Figure 8E

[0119] Therefore, as shown in Figure 8E , in some embodiments, the hydrogel 62 is disposed on the channel 31L to form a sensing arm, and the other channel 32L that is not covered by the hydrogel forms a reference arm.

[0120] Figure 9 is a perspective view showing the biochip 104 according to some embodiments of the present disclosure. It should be noted that, for the sake of brevity, some components of the biochip 104 have been omitted in the figure. As shown in Figure 9 , in some embodiments, the light source S3 emits light to the grating coupler 31 of the channel waveguide 30", and the sensing light with a wavelength of λ3 passes through the channels 31L and 32L. Figure 9

[0121] After loading the biological sample and washing, the specific analyte can be immobilized on the hydrogel. Next, by coupling the sensing light with a wavelength of λ3 into the channel waveguide 30", the sensing light can propagate in the channel waveguide 30" and be separated into each channel. If the specific analyte exists in the biological sample, the hydrogel 62 on the channel 31L will capture the analyte and increase the refractive index, which causes a wavelength shift sf (by comparing the distribution graph D1 with the distribution graph D2). By using the three-dimensional hydrogel 62 with functional molecules, the number of analyte binding can be increased by several times compared to the number of analyte binding on a two-dimensional surface. Therefore, the refractive index change can be increased, thereby improving the sensitivity.

[0122] Figure 10 is a schematic view showing the effect of glucose on the functional molecules in the hydrogel 62 of the biochip 102. Figure 11 is a glucose response spectrum. Figure 12 is a schematic view showing the application of the biochip 106 on the skin SK of a living body according to some embodiments of the present disclosure.

[0123] As shown in Figure 10 ​​As shown, the biochip 102 can form multiple hydrogel line arrays, and the hydrogels on different channels (e.g., hydrogels 61, 62, 63, 64, and 65) contain different functional molecules or concentrations. Thus, the biochip 102 can be used to detect the concentration gradient of a target biological sample or to detect the presence of various specific substances in a target biological sample. One possible implementation is to repeat the microneedle structure (by using a microneedle mold, injecting a hydrogel precursor, and then using a UV light to crosslink the hydrogel under the microneedle mold to form the microneedle MN) to integrate the microneedle onto the biochip 102. Concanavalin A-dextran FRET complexes with different concentrations can be embedded into the hydrogels 61, 62, 63, 64, and 65. Concanavalin A (labeled as CA1 in Figure 7 As shown, the biochip 102 can form multiple hydrogel line arrays, and the hydrogels on different channels (e.g., hydrogels 61, 62, 63, 64, and 65) contain different functional molecules or concentrations. Thus, the biochip 102 can be used to detect the concentration gradient of a target biological sample or to detect the presence of various specific substances in a target biological sample. One possible implementation is to repeat the microneedle structure (by using a microneedle mold, injecting a hydrogel precursor, and then using a UV light to crosslink the hydrogel under the microneedle mold to form the microneedle MN) to integrate the microneedle onto the biochip 102. Concanavalin A-dextran FRET complexes with different concentrations can be embedded into the hydrogels 61, 62, 63, 64, and 65. Concanavalin A (labeled as CA1 in Figure 10 Concanavalin A (labeled as CA1 in Figure 11 As shown, the biochip 102 can form multiple hydrogel line arrays, and the hydrogels on different channels (e.g., hydrogels 61, 62, 63, 64, and 65) contain different functional molecules or concentrations. Thus, the biochip 102 can be used to detect the concentration gradient of a target biological sample or to detect the presence of various specific substances in a target biological sample. One possible implementation is to repeat the microneedle structure (by using a microneedle mold, injecting a hydrogel precursor, and then using a UV light to crosslink the hydrogel under the microneedle mold to form the microneedle MN) to integrate the microneedle onto the biochip 102. Concanavalin A-dextran FRET complexes with different concentrations can be embedded into the hydrogels 61, 62, 63, 64, and 65. Concanavalin A (labeled as CA1 in Figure 11As shown, by observing the change in the intensity ratio of the emission peaks at 670 nm and 600 nm, the glucose content in the interstitial fluid (ISF) can be inferred, thus reflecting the blood glucose concentration in the skin. Furthermore, by using a hydrogel array of concanavalin A-dextran FRET complexes with different initial concentrations, multi-point detection can be performed on a single glucose sample, thereby improving the accuracy of the measurement.

[0124] When the microneedle MN pierces the skin, it absorbs intercellular fluid (ISF) (e.g., glucose, lactic acid, or alcohol) and diffuses these substances into the hydrogel 61–65. Since the amount of ISF absorbed after microneedle insertion is typically only a few microliters, glucose will replace the DG sites in the original DG+CA1 or DG+CA2 complex. When excited by green light, the intensity ratio at 660 / 670 nm changes, which can be used to determine the amount and concentration of glucose in the test sample.

[0125] like Figure 12 As shown, the biochip 106 may have the same characteristics as... Figure 7 The biochip 102 shown has a similar structure. In some embodiments, the biochip 106 further includes microneedle structures 69 that connect hydrogels 61, 62, 63, and 64 to external components (e.g., the skin SK of an organism). The microneedle structures 69 integrated on the biosensor (including the biochip 106) facilitate penetration of the skin and extraction of intercellular fluid (e.g., glucose, lactic acid, or alcohol) for physiological signal monitoring.

[0126] As described above, the biochip according to embodiments of this disclosure includes a waveguide core layer. The waveguide core layer includes at least one grating coupler for coupling light to crosslink the hydrogel, thereby improving the selective modification and / or multiple screening capabilities of the biochip through a thin layer of hydrogel.

[0127] The foregoing outlines features of several embodiments to enable those skilled in the art to better understand the views expressed in the embodiments of this disclosure. Those skilled in the art should understand that they can design or modify other processes and structures based on the embodiments of this disclosure to achieve the same purpose and / or advantages as the embodiments described herein. Those skilled in the art should also understand that such equivalent structures do not depart from the spirit and scope of this disclosure, and that they can make various changes, substitutions, and replacements without departing from the spirit and scope of this disclosure. Therefore, the scope of protection of this disclosure is determined by the appended claims. Furthermore, although this disclosure has been given above with reference to several embodiments, it is not intended to limit the scope of this disclosure.

[0128] Reference throughout this specification to features, advantages, or similar language does not mean that all of the features and advantages that can be achieved in accordance with the present disclosure should be or are in any single implementation of the disclosure. Rather, language relating to the features and advantages is understood to mean that a specific feature, advantage, or characteristic described in connection with an implementation can be included in at least one implementation of the disclosure. Thus, discussions of features and advantages, and similar language, throughout this specification may, but do not necessarily, represent that a similar implementation can be made of the disclosure.

[0129] Furthermore, the described features, advantages, and characteristics of the disclosure can be combined in any suitable manner in one or more embodiments. One skilled in the relevant art will recognize, in light of the description herein, that the disclosure can be practiced without one or more of the specific features or advantages of a particular implementation. In other instances, additional features and advantages can be recognized in certain embodiments that can not be present in all implementations of the disclosure.

Claims

1. A biochip, comprising: One substrate; A waveguide core layer is disposed above the substrate, wherein the waveguide core layer includes a first grating coupler; as well as A hydrogel is cross-linked by a hydrogel cross-linking light, which is coupled through the first grating coupler.

2. The biochip as claimed in claim 1, wherein the substrate has a photoelectric conversion element, and the hydrogel corresponds to the photoelectric conversion element.

3. The biochip as described in claim 2, further comprising: An upper cladding layer is disposed on the waveguide core layer. The upper cladding layer includes a nanopore disposed above the photoelectric conversion element, wherein the upper cladding layer exposes the first grating coupler, and the hydrogel is disposed at the bottom of the nanopore.

4. The biochip as claimed in claim 3, wherein the thickness of the upper coating layer is greater than 50 nanometers, and when the thickness of the upper coating layer is greater than 100 nanometers, the distance between the uppermost layer of the hydrogel and the waveguide core layer is less than 100 nanometers.

5. The biochip of claim 3, wherein the substrate has a plurality of photoelectric conversion elements, and the upper coating layer includes a plurality of nanopores disposed above the plurality of photoelectric conversion elements, and a plurality of hydrogels are disposed at the bottom of the plurality of nanopores.

6. The biochip of claim 1, wherein the first grating coupler is used to couple a hydrogel crosslinking light and a sensing light, and the wavelength of the hydrogel crosslinking light is shorter than the wavelength of the sensing light.

7. The biochip as claimed in claim 1, wherein the first grating coupler is used to couple a hydrogel crosslinked light, and the waveguide core layer further includes: A second grating coupler is disposed on the other side of the first grating coupler, wherein the second grating coupler is used to couple a sensing light, and the wavelength of the hydrogel crosslinked light is shorter than the wavelength of the sensing light.

8. The biochip of claim 1, wherein the waveguide core layer is formed as a channel waveguide, and the channel waveguide comprises: At least one first grating coupler is disposed on the upper side of one side of the substrate; A second grating coupler is disposed on the upper side of the other side of the substrate; and Multiple channels connect the at least one first grating coupler to the second grating coupler.

9. The biochip of claim 8, wherein it has a plurality of interleaved first grating couplers, and the channel waveguide further comprises: A beam splitter is connected to the second grating coupler and the plurality of channels. The first grating coupler is arranged in an array.

10. The biochip of claim 8, wherein the hydrogel is disposed on all channels, and the hydrogel on different channels has different functional molecules or concentrations.

11. The biochip of claim 8, wherein the at least one first grating coupler is used to couple light of the same or shorter wavelength as the light coupled through the second grating coupler.

12. The biochip of claim 8, wherein the hydrogel is disposed on one of the plurality of channels to form a sensing arm, while the other channels without the hydrogel form a reference arm.

13. The biochip of claim 1, wherein the hydrogel comprises gelatin methacrylate, polyethylene glycol diacrylate, or hyaluronic acid.

Images