TWI593951B - Sensing chip - Google Patents

Description

Sense wafer

The present invention relates to sensing wafers, and more particularly to the manner in which their nanostructures are formed.

In biomedical testing, both food safety and cancer screening are currently based on Enzyme-linked immunosorbent assay (ELISA). Although the current ELISA technology has the advantage of high sensitivity, the reagent kits used are expensive, the detection steps are cumbersome and time consuming, and the target analyte needs to be attached to a biotag (such as a fluorescent molecule) or an enzyme is attached. The color reaction, while the fluorescent molecules not only interfere with the activity of the target molecule, but most of the fluorescent molecules have problems of photobleaching or fluorescent scintillation, which makes the ELISA method easy to produce at low concentration measurement. error.

The localized Surface Plasmon Resonances (LSPR) principle of the wafer can achieve the effect of calibration-free and fast detection, which utilizes the surface plasma resonance spectrum of the metal nanostructure. Since LSPR is sensitive to changes in the refractive index of the metal interface, it can be used to detect trace analytes (such as antigens or antibodies) adsorbed within a distance of several tens of nanometers from the surface of the structure. In LSPR, the surface plasma resonance spectrum of the metal nanostructure is a key factor in detecting sensitivity to the environmental refractive index change (ie, Δλ/Δn). In addition, when the half-height of the resonance spectrum is narrower, the resolution of the spectrum is higher, and the detection effect can be improved. Formula 1 is a wafer Definition of quality factor (Figure of Merit, FoM).

Compared with the existing ELISA technology, the LSPR technology is a fluorescence-free cursor-based detection method, which can shorten the detection process and time, and does not encounter the problem of three-dimensional space barrier of grafting of secondary antibodies (including fluorescent molecules). However, the sensitivity of LSPR wafers compared with ELISA is still insufficient. The main reason is that in addition to the general plasmonic resonance spectrum, it is also a major focus on whether the analyte can be close to the hot spot position on the nanostructure to produce an effective spectral shift.

There is a need for a new LSPR structure to increase the sensitivity of the object to be measured and to increase the spectral discrimination rate (reducing the full width at half maximum of the resonant wavelength), thereby measuring a lower concentration of the analyte.

An embodiment of the invention provides a sensing wafer, comprising: a substrate; and a plurality of nanostructures periodically arranged on the substrate, wherein each nanostructure comprises: a bottom metal layer on the substrate; an intermediate dielectric layer, Located on the bottom metal layer; and the top metal layer on the intermediate dielectric layer; wherein the area of the bottom metal layer is greater than the area of the top metal layer.

The sensing wafer raises the hot spot position from the substrate to a top metal layer to which the object to be tested is easily attached. The nano-structure period on the sensing wafer can mutually couple the resonant mode (LSPR mode) of the structural unit itself with the Rayleigh anomaly provided by the periodic structure to generate a Fino resonance mode (Fano resonance) Mode) to reduce the Full Width Half Maximum (FWHM) of the formant, thereby increasing the detection limit of the wafer.

P‧‧ cycle

1‧‧‧Sensor wafer

10‧‧‧Substrate

11‧‧‧Photoresist layer

13‧‧‧ openings

15‧‧‧ bottom metal layer

17‧‧‧Intermediate dielectric layer

19‧‧‧Top metal layer

20‧‧‧Nano structure

41‧‧‧Modifier

43‧‧‧Test object

61‧‧‧ Hotspots

1A to 1D are cross-sectional views showing a process of sensing a wafer in an embodiment of the present invention.

1E to 1G are cross-sectional views of the nanostructure in the embodiment of the present invention.

2A to 2B are top views of the periodically arranged nanostructures in the embodiment of the present invention.

3A to 3C are top views of the nanostructure in the embodiment of the present invention.

Fig. 4 is a schematic view showing the use of a modifier to bond a test object to a top metal layer of a nanostructure in the embodiment of the present invention.

5A and 5B are cross-sectional views of the nanostructure in the embodiment of the present invention.

6A and 6B are diagrams showing the simulated spectrum of the analyte on the nanostructure in the embodiment of the present invention.

7A and 7B are simulated plasmon resonance spectra of a nanostructure in an embodiment of the present invention.

Figure 8 is a graphical representation of the spectral changes of the same nanostructure in different media in an embodiment of the invention.

Figure 9 is a graph showing the change in the crystal structure of an intermediate dielectric layer having different thicknesses in the same medium in the embodiment of the present invention.

10A and 10B are cross-sectional views of the nanostructure in the embodiment of the present invention.

1A to 1D are cross-sectional views showing a process of sensing the wafer 1 in an embodiment of the present invention. As shown in FIG. 1A, the substrate 10 is first provided, and the photoresist layer 11 is formed on the substrate 10. The substrate 10 can be a dielectric material such as polyethylene terephthalate (PET), polymethyl methacrylate (PMMA), yttrium oxide (SiO ₂ ), alumina (Sapphire), glass, or other common dielectrics. material. The refractive index n _{s of the} substrate 10 is between 1.2 and 4.5. The refractive index n _{s of the} substrate 10 is related to the plasmon resonance wavelength of the nanostructure 20 to be described later. If the refractive index n _{s of the} substrate 10 is too large, the plasmon resonance wavelength is red-shifted to the infrared light range, which causes an increase in the cost of the spectrometer device.

Next, as shown in FIG. 1B, the photoresist 11 is selectively exposed by a photomask, and after development, the patterned photoresist layer 11 is formed to form a periodically arranged opening 13. The photoresist layer 11 can be a positive photoresist or a negative photoresist, and a corresponding photomask is used. Adjusting the process parameters allows the patterned photoresist layer 11 to have its opening 13 having a lower width and a lower (undercut) shape, and the side walls of the opening 13 may be curved (see FIG. 1B) or planar (not shown).

Next, as shown in FIG. 1C, the bottom metal layer 15, the intermediate dielectric layer 17, and the top metal layer 19 are sequentially deposited in the opening 13 and the photoresist layer 11. The bottom metal layer 15 may be gold, silver, aluminum, chromium, copper, titanium, or an alloy of the above. In an embodiment of the invention, the bottom metal layer 15 and the top metal layer 19 may have the same composition. In an embodiment of the invention, the bottom metal layer 15 has a thickness between 1 nm and 40 nm. If the thickness of the bottom metal layer 15 is too thin, it is not easy to form a uniform film. If the thickness of the bottom metal layer 15 is too thick, the microstructure cannot be produced by a lift-off method. The intermediate dielectric layer 17 can be aluminum oxide, tantalum oxide, tantalum nitride, or a combination thereof. In an embodiment of the invention, the intermediate dielectric layer 17 has a thickness between 1 nm and 10 nm. If the thickness of the intermediate dielectric layer 17 is too thin, it is not easy to form a uniform film. If the thickness of the intermediate dielectric layer 17 is too thick, the surface plasmon resonance mode coupling effect of the bottom metal layer and the top metal layer is poor, and the regulation of the structure spectrum is degraded. The top metal layer 19 can be gold, silver, aluminum, chromium, copper, titanium, or an alloy of the foregoing. In the present invention In an embodiment, the top metal layer 15 has a thickness between 2 nm and 40 nm. If the thickness of the top metal layer 15 is too thin, it is not easy to form a uniform film. If the thickness of the top metal layer 15 is too thick, the microstructure cannot be produced by a lift-off method.

Next, as shown in FIG. 1D, the photoresist layer 11 and the material deposited thereon are stripped, and the bottom metal layer 15, the intermediate dielectric layer 17, and the nanostructure 20 stacked with the top metal layer 19 are left in the opening 13. In an embodiment of the invention, the nanostructure 20 has a width between 50 nm and 1000 nm. If the width of the nanostructure 20 is too small, structural uniformity is not easily controlled. If the width of the nanostructure 20 is too large, the resonance spectrum falls at the wavelength of the infrared light, resulting in an increase in the cost of the spectrometer. In an embodiment of the invention, the width of the nanostructure 20 is greater than or equal to the height of the nanostructure 20 (the total thickness of the bottom metal layer 15, the intermediate dielectric layer 17, and the top metal layer 19). If the height of the nanostructure 20 is greater than the width of the nanostructure 20, the aspect ratio is too large to cause difficulty in the process.

Since the openings 13 of the photoresist layer 11 are periodically arranged, the corresponding nanostructures 20 are also periodically arranged, and the period P is between 100 nm and 2000 nm. If the period P is too large, the corresponding Rayleigh ananomy occurs in the infrared range. If the period P is too small, the corresponding Rayleigh ananomy occurs in the ultraviolet range and is too small to be easily fabricated. The top view of the periodic arrangement of the nanostructures 20 described above may be a hexagonal arrangement as shown in Figure 2A, a rectangular arrangement as shown in Figure 2B, or other suitable arrangement. In addition, the top view of the nanostructure 20 may be circular as shown in FIG. 3A, square as shown in FIG. 3B, triangular as shown in FIG. 3C, or other suitable top view. The plasmon resonance wavelength λ _LSP of the periodically arranged nanostructure 20 is between 0.85 n _s × P and 1.15 n _s × P. If the plasmon resonance wavelength λ _{LSP is} not in this interval, the resonance spectrum is broadened, and the spectral discrimination rate of the sensing wafer is lowered.

As shown in FIG. 1D, the area of the bottom metal layer 15 is larger than the area of the top metal layer 19. In an embodiment of the invention, the bottom metal layer 15 has a width between 50 nm and 1000 nm. If the width of the bottom metal layer 15 is too large, the plasmon resonance wavelength is red-shifted to the infrared range, which may result in an increase in spectrometer equipment cost. If the width of the bottom metal layer 15 is too small, structural uniformity is not easily controlled. In an embodiment of the invention, the width of the intermediate dielectric layer 17 is between 40 nm and 800 nm. If the width of the intermediate dielectric layer 17 is too large or too small, the structure is not easy to fabricate. In an embodiment of the invention, the width of the top metal layer 19 is between 10 nm and 700 nm. If the width of the top metal layer 19 is too large, the plasmon resonance wavelength is red-shifted to the infrared range, which may result in an increase in the cost of the spectrometer device. If the width of the top metal layer 19 is too small, structural uniformity is not easily controlled.

Although the side view shape of the nanostructure 20 in Fig. 1D is tapered, the side view shape may be a hill shape as shown in Fig. 1E, a stepped shape as shown in Fig. 1F, or other suitable ones. Side view shape. It will be understood that although the nanostructure 20 in the drawings has curved side walls, the flat side walls may also be as shown in FIG. 1G. In an embodiment of the invention, the top of the nanostructure 20 may be a rounded arc rather than a flat top.

The sensing wafer 1 can be directly placed in a medium (such as water or air) containing a substance to be tested, and is subjected to a force (such as van der Waals force or physical adsorption) between the surface of the nanostructure 20 and the object to be tested. The object is fixed on the nanostructure 20, and then the peak shift of the absorption spectrum of the wafer in different media is measured, and the equivalent refractive index of the analyte is quantified, and the concentration of the analyte is calculated accordingly. In an embodiment of the present invention, the modifier 41 may be further bonded to the surface of the top metal layer 19 to make the object to be tested. 43 is bonded to the surface of the top metal layer 19 via the modifier 41 as shown in FIG. The kind of the modifier is related to the types of the top metal layer 19 and the object to be tested 43. For example, when the top metal layer 19 is gold and the analyte 43 is an antibody, the modifier 41 may have a thiol bond at one end and a carboxyl group (-COOH) or an amine group at the other end (- Small molecules of NH2), such as cysteamine, 11-mercaptoundecanoic acid (11-MUA), or 11-Amino-1-undecanethiol hydrochloride Wait.

The above and other objects, features, and advantages of the present invention will become more apparent and understood.

Example Example 1

A nanostructure (MIM) for forming gold/alumina/gold on a ruthenium oxide substrate is shown in FIG. 5A, and a single-layered gold nanostructure is formed on another ruthenium oxide substrate as shown in FIG. 5B, and compared. The distribution of hotspots 61 of both structures. In the nanostructure of Fig. 5A, the thickness of the bottom metal layer (gold) is 10 nm, the thickness of the intermediate dielectric layer (alumina) is 20 nm, and the thickness of the top metal layer (gold) is 40 nm. The nanostructure of Fig. 5A has a width of 200 nm and an arrangement period of 650 nm. The thickness of the single-layered gold nanostructure of Fig. 5B is 70 nm. The nanostructure of Fig. 5B has a width of 200 nm and an arrangement period of 650 nm.

The hot spot of the single-layer metal nanostructure of Fig. 5B is mainly located at the tip end of the yttrium oxide substrate and the gold nanostructure. The hot spot of the MIM nanostructure of Fig. 5A is distributed at the tip end of the yttrium oxide substrate and the nanostructure junction, and the tip metal layer (gold) and the intermediate dielectric layer (alumina) are joined to each other at the tip end. More intense hotspot distribution.

Then, the characteristic spectrum of the above-mentioned nanostructure corresponding to the object to be tested is simulated by the Finite Difference Time Domain (FDTD). The refractive index of the buffer (medium) was set to 1.33, the refractive index of the analyte (antibody) was set to 1.5, and the analyte was uniformly deposited on the surface of the nanostructure at a thickness of 20 nm, and the simulated spectrum was as shown in FIGS. 6A and 6B. . From the comparison of Figures 6A and 6B, the MIM nanostructure can effectively improve the sensitivity of the wafer (about 6.7 times).

Further analysis of the influence of the MIM structure on the distribution of the analyte, about 75% of the spectral change comes from the contribution of the analyte grafted to the upper half of the nanostructure. In contrast, the contribution of the analyte grafted to the upper half of the single layer of the gold nanostructure is only 20%. Since the antibody in the liquid is randomly collided with the nanostructure by Brownian motion during the actual grafting process, the antibody grafted to the upper half of the nanostructure first forms a steric barrier antibody close to the lower half of the nanostructure. Therefore, adjusting the hot spot position from the bottom of the nanostructure to the upper half of the nanostructure (such as between the top metal layer and the intermediate dielectric layer) can effectively increase the probability of the object to be tested attached to the hot spot, thereby improving the object to be tested. Detection limit. It can be seen from the above that the MIM nanostructure has higher detection sensitivity and detection limit at the same distribution density and size than the single-layer metal nanostructure.

Example 2

The MIM nanostructure of Example 1 was taken, the period was adjusted and the plasmon resonance spectrum was simulated as shown in Fig. 7A. The simulation results show that the larger the half-height of the formant is, the smaller the period is. This is because the LSPR mode of the structural unit is diffracted by the periodic structure when the period is larger. Rayleigh anomaly mode two conditions are close to each other and coupled, as in 7B The figure shows. As can be seen from Fig. 7B, the optimum period of the above nanostructure is about 650 nm.

Example 3

The spectral change of the nanostructure in the environment of air (n=1) and water (n=1.33) is shown in Fig. 8. It can be seen from the figure that the spectrum has two characteristic peaks (mode1, mode2). , mode1 is more sensitive to environmental refractive index changes than mode2. Figure 9 shows the thickness of the top metal layer (15 nm) and the thickness of the bottom metal layer (15 nm) of the nanostructure in air, and the thickness of the intermediate dielectric layer of the nanostructure is changed to confirm the thickness of the intermediate dielectric layer to the characteristic spectrum. Impact. It can be seen from the simulation results that the thicker the dielectric layer is, the closer the spectral distances of the two features are, and finally even overlap. On the contrary, when the thickness of the dielectric layer is thinner, spectral separation occurs due to strong surface plasma coupling of the upper and lower metal layers. Since the sensor only uses mode1, in order to avoid the interference of mode 2, the thickness of the intermediate dielectric layer is not too large (preferably less than 10 nm), so that the discrimination of the characteristic spectral position is not disturbed due to the overlap of mode1 and mode2.

Example 4

A nanostructure (MIM) of gold/alumina/gold formed on a ruthenium oxide substrate is shown in FIG. 10A, and a gold/alumina/gold nanostructure (MIM) is formed on another ruthenium oxide substrate. As shown in Fig. 10B, the thickness of the bottom metal layer (gold) is 10 nm, the thickness of the intermediate dielectric layer (alumina) is 25 nm, and the thickness of the top metal layer (gold) is 10 nm. The nanostructures of FIGS. 10A and 10B have a width of 200 nm and an arrangement period of 600 nm. As shown in Figures 10A and 10B, the difference between the two MIM nanostructures is that the cross-sectional shape of Figure 10A is semi-elliptical, that is, the area of the top metal layer (width is 140 nm) is smaller than the area of the bottom metal layer (width is 200 nm). And the cross-sectional shape of FIG. 10B is a rectangle, that is, the area of the top metal layer is equal to the area of the bottom metal layer. Calculated at resonance wavelengths at different refractive indices The sensitivity of the wafer to the change in refractive index was 269 nm/RIU and 288 nm/RIU, respectively, and it was found that the sensitivity of the nanostructure of Fig. 10B was about 7% higher than that of the nanostructure of Fig. 10A. The properties of the above nanostructures are compared as shown in Table 1.

As can be seen from the first table, the nanostructure having a larger area of the underlying metal layer than the area of the top metal layer has high sensitivity.

P‧‧ cycle

1‧‧‧Sensor wafer

10‧‧‧Substrate

15‧‧‧ bottom metal layer

17‧‧‧Intermediate dielectric layer

19‧‧‧Top metal layer

20‧‧‧Nano structure

Claims (13)

A sensing wafer includes: a substrate; and a plurality of nanostructures periodically arranged on the substrate, wherein each of the nanostructures comprises: a bottom metal layer on the substrate; an intermediate dielectric a layer on the bottom metal layer; and a top metal layer on the intermediate dielectric layer; wherein the top metal layer has an area smaller than an area of the bottom metal layer, wherein the bottom metal layers of different nano structures are not connected, And the intermediate dielectric layers of the different nanostructures are not connected, wherein the intermediate dielectric layer has a thickness of between 1 nm and less than 10 nm. The sensing wafer of claim 1, wherein the nanostructures have a plasmon resonance wavelength λ _LSP and an aligned period P, the substrate having a refractive index n _s and a period P between 100 nm and Between 2000 nm, the refractive index n _{s is} between 1.2 and 4.5, and the λ _{LSP is} between 0.85 n _s × P and 1.15 n _s × P. The sensing wafer of claim 1, wherein the substrate comprises a dielectric material. The sensing wafer of claim 1, wherein the periodic arrangement of the nanostructures comprises a rectangular arrangement or a hexagonal arrangement. The sensing wafer of claim 1, wherein the top view shape of the nanostructures comprises a circle, a square, or a triangle. The sensing wafer of claim 1, wherein the side views of the nanostructures comprise a cone shape, a hill shape, or a step shape. The sensing wafer of claim 1, wherein the nanostructures have a width of between 50 nm and 1000 nm. The sensing wafer of claim 1, wherein the width of the nanostructures is greater than or equal to the height of the nanostructures. The sensing wafer of claim 1, wherein the intermediate dielectric layer comprises aluminum oxide, tantalum oxide, tantalum nitride, or a combination thereof. The sensing wafer of claim 1, wherein the top metal layer and the bottom metal layer each comprise gold, silver, aluminum, chromium, copper, titanium, or an alloy thereof. The sensing wafer of claim 1, wherein the top metal layer has a thickness of between 1 nm and 50 nm. The sensing wafer of claim 1, wherein the bottom metal layer has a thickness of between 1 and 50 nm. The sensing wafer of claim 1, further comprising a modifying agent bonded to the surface of the top metal layer, such that a test object is bonded to the surface of the top metal layer via the modifying agent.