New terahertz sensor for highly sensitive and label-free detection of ultra-trace samples

Abstract

The present invention discloses a novel high-sensitivity terahertz sensor that can be used for label-free ultra-trace sensing, including a periodic basic structure and a sample well constructed on the basic structure, wherein the unit structure of the periodic basic structure is a quasi-electromagnetic induction transparent structure composed of a metal wire and a resonant ring with two openings on both sides, and the sample well is a pair of square well structures constructed on the upper layer of the double-sided resonant ring openings for sample placement. The present invention also discloses a method for preparing the novel terahertz sensor and a method for using the novel terahertz sensor for ultra-trace detection. The present invention realizes label-free high-sensitivity detection of ultra-trace biological samples by placing ultra-trace biological samples in the sample well of the terahertz sensor.

Description

Technical Field

[0001] The invention relates to a terahertz sensor, in particular to a novel terahertz sensor for detecting ultra-trace samples with high sensitivity and without labeling. Background Art

[0002] In the past few decades, terahertz technology has developed rapidly, and technologies such as terahertz imaging and terahertz time-domain spectroscopy have emerged one after another. Terahertz for biomedical applications has also become an important scenario. The photon energy of terahertz is only in the meV level, which is much lower than that of X-rays. It will not cause ionization damage to the object being tested and is suitable for non-destructive testing of living bodies. The rotation, vibration transition, and weak interaction energy levels of a large number of organic molecules are just in the terahertz band, so terahertz technology is conducive to biological research applications.

[0003] Designing terahertz functional devices that can be used to detect biological samples is very important in the biomedical field. The widely used flow cytometers for labeling and measuring biological molecules are destructive, cannot perform dynamic observations, are expensive and time-consuming, and require a large amount of samples. Although label-free detection can be achieved using high-quality optical microcavity mirrors, this method has poor thermal stability, complex preparation, and difficulty in integrating three-dimensional structures, making it difficult to be applied in practice.

[0004] Based on metamaterials and plasmon structures, the interaction between light and the sample being tested can be enhanced, thereby causing changes in the spectral response, and label-free sensing of biological samples can be achieved. However, due to the limitations of the metamaterial infrastructure and sample coating methods, the sensitivity of related sensors is generally around 50GHz / (RIU·mm3) (RIU, Refractive Index Unit, indicating the unit refractive index change), and it is difficult to achieve high-sensitivity detection for ultra-trace samples with a total volume of less than 0.01ml. Summary of the invention

[0005] In view of the problems and shortcomings of the above-mentioned prior art, the purpose of the present invention is to provide a new terahertz sensor for highly sensitive and label-free detection of ultra-trace samples and a preparation method and a detection method thereof, so as to achieve highly sensitive detection of ultra-trace samples.

[0006] Technical Solution

[0007] To achieve the above-mentioned invention purpose, the first technical solution adopted by the present invention is a new type of terahertz sensor for high sensitivity and label-free measurement of ultra-trace samples, including a basic periodic structure of electromagnetically induced transparency like (EIT-like) metamaterial (artificial electromagnetic medium, metamaterial), and a sample trap constructed on the upper layer of the opening, wherein the unit structure of the basic periodic structure is a metal wire located in the center and a pair of splitting ring resonators (SRRs) symmetrical about the metal wire. The present invention utilizes the characteristics that the electric field intensity at the opening of the electromagnetically induced transparent metamaterial is the strongest and is most sensitive to changes in the external dielectric environment, and constructs a sample trap on the upper layer of the opening to detect samples with a total volume of less than 0.01 ml in the sample trap.

[0008] Furthermore, the bottom of the electromagnetic induction transparent metamaterial is a dielectric substrate film.

[0009] Furthermore, the dielectric substrate film is made of polyimide and has a thickness of 5 μm.

[0010] Furthermore, the metal wire and the two open resonant rings are both made of gold, and have a thickness of 200 nm.

[0011] Furthermore, the material of the sample well is selected to be SU-8 photoresist.

[0012] The second technical solution adopted by the present invention is a method for preparing the novel terahertz sensor as described above, comprising the following steps:

[0013] (1) Cleaning a substrate for growing a terahertz sensor substrate;

[0014] (2) coating a polyimide film on the substrate to obtain a polyimide film with a thickness of 5 μm on the substrate as a base of the terahertz sensor, and drying the film;

[0015] (3) coating photoresist LOR10B on the polyimide film and drying;

[0016] (4) coating photoresist AZ1500 on the photoresist LOR10B and drying;

[0017] (5) exposing, developing, and drying the photoresists LOR10B and AZ1500;

[0018] (6) evaporating a metal film on the photoresist AZ1500 and the exposed polyimide film;

[0019] (7) soaking the substrate after the metal film is evaporated in an N-methylpyrrolidone solution to remove the residual photoresist and the metal attached to the photoresist, then washing it with anhydrous ethanol and deionized water, and drying it to obtain an electromagnetically induced transparent metamaterial including a basic periodic structure;

[0020] (8) coating the substrate with the metal film with SU-8 photoresist and drying;

[0021] (9) exposing and developing the SU-8 photoresist, and cleaning and drying the same to obtain a sample well;

[0022] (10) Removing the substrate: peeling off the substrate and the polyimide film with the structure.

[0023] The third technical solution of the present invention is a method for using the terahertz sensor as described above for ultra-trace biological sample detection, wherein a biological sample with a total volume of less than 0.01 ml is placed in the sample well of the terahertz sensor. The resonance frequency shift value provided by the novel terahertz sensor exceeds 42 GHz, and the resonance amplitude change exceeds 22%, which is sufficient for measurement by a terahertz time-domain spectroscopy system.

[0024] Beneficial Effects

[0025] Compared with previous results, the terahertz sensor designed in this invention adopts a method of constructing a sample well on the upper layer of the most sensitive opening of the surface of the electromagnetic induction transparent metamaterial, which greatly improves the sensitivity of sample detection per unit volume, up to 5538GHz / (RIU·mm 3 ), can be used for label-free measurement of ultra-trace biological samples with a total volume of less than 0.01 ml. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is a three-dimensional diagram of the new terahertz sensor unit structure of the present invention.

[0027] Figure 2 This is a side view of the new terahertz sensor unit structure of the present invention.

[0028] Figure 3 The transmission spectrum is calculated after placing an ultra-trace biological sample in the sample well of the novel terahertz sensor of the present invention. DETAILED DESCRIPTION

[0029] The present invention is further explained below in conjunction with the accompanying drawings and specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of use of the present invention. After reading the present invention, various equivalent forms of modifications to the present invention by those skilled in the art all fall within the scope defined by the claims attached to this application.

[0030] 1. Design of a highly sensitive terahertz sensor that can detect ultra-trace amounts of biological samples without labeling

[0031] According to Figure 1 The terahertz sensor structure design simulation shown in the figure has a basic unit structure consisting of a metal wire in the center and two open resonant rings symmetrical about the metal wire on both sides. After selecting the resonant frequency and analyzing the electric field coupling between the metal wire and the open resonant ring, the parameters of the final structure are obtained. Figure 1 As shown, combined Figure 2 Side view auxiliary reference, the bottom is a polyimide (PI) substrate 1, thickness H 1 =5μm. The metal layer (titanium / gold) 2 includes a metal wire 4 and SRR rings 5 ​​on both sides. The specific parameters are the metal wire length l = 104μm, the outer edge length a = 30μm, the SRRs opening width g = 2μm, the spacing between the metal wire and the two SRR rings s = 7.5μm, the line width w is 5μm, and the total thickness of the metal layer 2 H 2 = 210nm, of which the adhesion layer is titanium 10nm and gold 200nm. The sample well 3 on the upper layer of each SRR ring opening is made of common SU-8 photoresist, with an outer side length of b = 14μm, a thickness of d = 2μm, and a height H 3 =10μm. The selection of various materials is for the feasibility of future experimental work.

[0032] 2. Processing and manufacturing of high-sensitivity, label-free terahertz sensors

[0033] The specific parameters of the device determined by the electromagnetic field simulation software are as follows Figure 1 As shown, draw the mask file, and then the specific steps of making the new sensor are as follows:

[0034] (1) Cleaning the substrate

[0035] First, use acetone, anhydrous ethanol, and deionized water to ultrasonically clean a substrate with a size of 15mm×15mm and a thickness of 500μm, then blow it dry with an air gun and heat it on a drying table to remove the water attached to the substrate. The substrate is used here because the polyimide medium substrate used in this sensor is a flexible material and needs to be coated, so a hard substrate is needed as a carrier during the production process to avoid overall deformation of the device during the production process. The substrate material can be selected from common hard substrates, such as silicon, quartz, magnesium oxide substrates, etc.

[0036] (2) Spin coating of polyimide dielectric film

[0037] A polyimide film with a viscosity of 5600 centipoise was spin-coated on the substrate, and the pre-rotation speed was set to 600 rpm and the steady rotation speed was set to 4000 rpm for 6 s and 60 s respectively. After the coating was completed, the film was placed on a drying table for heating at 80° C. for 1 h, 120° C. for 1 h, 180° C. for 1 h, and 250° C. for 2 h until it was completely cured, thereby obtaining a polyimide film with a thickness of 5 μm on the substrate as the substrate of the sensor;

[0038] (3) Spin coating two layers of photoresist

[0039] On the polyimide film, two layers of photoresist LOR10B and AZ1500 were spin-coated in sequence. The lower layer of photoresist LOR10B was spin-coated first, and the pre-rotation speed of the coating machine was set to 600 rpm and the stable rotation speed was set to 4000 rpm for 6 seconds and 40 seconds respectively. After the completion, it was placed on a baking table and heated at 150°C for 5 minutes. Then, the second layer of photoresist AZ1500 was spin-coated with the same parameters, and after the completion, it was placed on a baking table and heated at 100°C for 2 minutes.

[0040] (4) Exposure and Development

[0041] Place the substrate with the photoresist spun on it into the laser direct writing lithography machine, and import the mask file you have drawn. Set the laser quality to high and the laser metering to 150mJ / cm 2 After photolithography, use positive photoresist developer for 15 seconds.

[0042] (5) Evaporated metal film

[0043] Metals are deposited on the developed substrate by magnetron sputtering. The metals are titanium and gold. First, a layer of titanium is deposited at a constant current of 0.4A at a pressure of 4mTorr under the protection of argon gas with a gas volume flow rate of 100sccm for 10s. The thickness of titanium is 10nm, which acts as an adhesion layer. The conductivity of the titanium film is not high and it is very thin. The effect on the terahertz wave is negligible. Therefore, the simulation does not consider the titanium layer. Under the protection of argon gas with a gas volume flow rate of 100sccm, a layer of gold is deposited at a constant power of 80w at a pressure of 4mTorr for 200s. The thickness of gold is 200nm.

[0044] (6) Stripping metal

[0045] The substrate after the metal film is evaporated is immersed in N-methylpyrrolidone solution for 24 hours to strip the photoresist LOR10B and AZ1500. When the photoresist is stripped, the metal on its surface is taken away. Two layers of photoresist are used to better strip the photoresist and its attached metal layer to ensure the structural integrity of the edge of the gold film. Then it is washed with anhydrous ethanol and deionized water in turn, and dried.

[0046] (7) Spin coating photoresist

[0047] SU-8 photoresist was spin-coated on the substrate with the metal structure, and the pre-rotation speed of the coating machine was set to 600 rpm and the steady rotation speed was set to 3000 rpm for 6 s and 60 s respectively. After the end, it was placed on a baking table and heated at 95° C. for 4 minutes.

[0048] (8) Exposure and Development

[0049] Place the substrate with SU-8 photoresist spin-coated into the laser direct writing lithography machine and import the mask file drawn. Select the laser quality as high and the laser metering as 150mJ / cm 2 During photolithography, it is necessary to pay attention to aligning the photolithography marks and to make the mask pattern correspond to the position of the metal structure. After photolithography, positive photoresist developer is used for development for 15 seconds, and then cleaned and dried to obtain the sample well structure.

[0050] (9) Removal of substrate

[0051] The polyimide film and the bottom substrate are directly peeled off gently from the four corners using tweezers to obtain a complete novel terahertz sensor according to the present invention.

[0052] After the above steps, the novel terahertz sensor with a sample well of the present invention can be obtained. The size of the metal structure covering part of the entire sensor is 12 mm×12 mm, and the corresponding period number is 100×100.

[0053] 3. Solutions for the detection of ultra-trace biological samples using terahertz sensors with high sensitivity and label-free detection of ultra-trace biological samples

[0054] A biological sample with a total volume of less than 0.01 ml and in the ultra-trace range is placed in the sample well of the terahertz sensor, and the transmission spectrum of the terahertz sensor is measured using a terahertz time-domain spectroscopy system. During the measurement, it is necessary to ensure that the polarization direction of the incident electric field of the terahertz wave is consistent with Figure 1 The directions shown remain the same.

[0055] 4. Detection results and discussion of terahertz sensors with high sensitivity and label-free detection of ultra-trace biological samples

[0056] The most important application aspect of the terahertz sensor designed by the present invention, which is highly sensitive and capable of measuring ultra-trace samples without labeling, is the sensing measurement of ultra-trace samples such as single cells. Figure 3 This is the terahertz transmission spectrum after placing an ultra-trace biological sample in the sample well. The radius of the biological cell used in the simulation is 5 μm. In the simulation, we use the verified double Debye dielectric relaxation model, respectively bring in the parameters of water, human skin and rat skin, and analyze the transmission spectrum of the terahertz sensor. Figure 3It can be seen that for different biological molecules, the frequency deviation is greater than 42 GHz and the amplitude difference is greater than 22%, which is much larger than the frequency resolution and amplitude resolution of the terahertz time domain spectroscopy system (TDS). This further shows that our design can be used for label-free measurement of ultra-trace biological samples.

[0057] In conclusion, the terahertz sensor with sample well installed based on electromagnetic induction transparent metamaterial designed on polyimide substrate mainly embodies the advantages of high sensitivity and label-free detection of ultra-trace biological samples. According to actual needs, the substrate thickness, metal structure parameters, sample well size, etc. can be optimized and designed, and terahertz sensors with other frequencies and higher sensitivity can also be obtained. Therefore, it is widely used in terahertz sensing and recognition.

Claims

1. New terahertz sensor with high sensitivity and label-free detection of ultra-trace samples, It is characterized in that The invention comprises an electromagnetic induction transparent metamaterial of a basic periodic structure and a sample well constructed on an upper layer, wherein the unit structure of the basic periodic structure is a metal wire located in the center and two open resonant rings symmetrical about the metal wire.

2. The novel terahertz sensor for high sensitivity and label-free measurement of ultra-trace samples according to claim 1, It is characterized in that The substrate of the electromagnetic induction transparent metamaterial is a dielectric substrate film.

3. The novel terahertz sensor for high sensitivity and label-free measurement of ultra-trace samples according to claim 2, It is characterized in that The dielectric substrate film is made of polyimide and has a thickness of 5 μm.

4. The novel terahertz sensor for high sensitivity and label-free measurement of ultra-trace samples according to claim 1, It is characterized in that The metal wire and the two open resonant rings are both made of gold, and have a thickness of 200 nm.

5. The novel terahertz sensor for high sensitivity and label-free measurement of ultra-trace samples according to claim 1, It is characterized in that A sample well is established on the upper layer of the split resonant rings on both sides.

6. The novel terahertz sensor for high sensitivity and label-free measurement of ultra-trace samples according to claim 1, It is characterized in that The sample well is made of SU-8 photoresist.

7. A method for preparing a terahertz sensor as claimed in any one of claims 1 to 6, comprising the following steps: (1) Cleaning a substrate for growing a terahertz sensor substrate; (2) coating a polyimide film on the substrate to obtain a polyimide film with a thickness of 5 μm on the substrate as a base of the terahertz sensor, and drying the film; (3) coating photoresist LOR10B on the polyimide film and drying; (4) coating photoresist AZ1500 on the photoresist LOR10B and drying; (5) exposing, developing, and drying the photoresists LOR10B and AZ1500; (6) evaporating a metal film on the photoresist AZ1500 and the exposed polyimide film; (7) soaking the substrate after the metal film is evaporated in an N-methylpyrrolidone solution to remove the residual photoresist and the metal attached to the photoresist, then washing it with anhydrous ethanol and deionized water, and drying it to obtain an electromagnetically induced transparent metamaterial including a basic periodic structure; (8) coating the substrate with the metal film with SU-8 photoresist and drying; (9) exposing and developing the SU-8 photoresist, and cleaning and drying the same to obtain a sample well; (10) Removing the substrate: peeling off the substrate and the structured polyimide film.

8. A method for using the terahertz sensor according to any one of claims 1 to 6 for ultra-trace biological sample detection, It is characterized in that Samples with a total volume less than 0.01 ml are placed in all sample wells of the terahertz sensor.

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