CN105019033A - DNA chip and detection method and production method thereof - Google Patents
DNA chip and detection method and production method thereof Download PDFInfo
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- CN105019033A CN105019033A CN201510437983.XA CN201510437983A CN105019033A CN 105019033 A CN105019033 A CN 105019033A CN 201510437983 A CN201510437983 A CN 201510437983A CN 105019033 A CN105019033 A CN 105019033A
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Abstract
The present invention discloses a DNA chip and a detection method and a production method thereof. The substrate of the DNA chip is a SERS substrate taking a noble metal nano array as a substrate; the noble metal nano array is divided into a plurality of areas, the surface of each area is modified and connected with a plurality of different DNA probes, so that the DNA chip contains different probe DNA, the probe DNA is used to detect a target DNA to produce a SERS signal, and based on the frequency change and magnitude difference of the SERS signal, the identification and quantitative detection of the target DNA can be achieved. The DNA chip is designed by use of the noble metal nano array and surface enhanced raman scattering for achievement of detection and analysis of the target DNA and genes. The present invention also discloses a detection method and a production method of the DNA chip.
Description
Technical field
The present invention relates to biological detection, biotechnology and field of nanometer technology, particularly relate to a kind of DNA chip, the detection method of this DNA chip, the making method of this DNA chip.
Background technology
DNA chip is the one of biochip also known as gene chip (genechip), refer to and a large amount of probe molecule is fixed on upholder, according to base pair complementarity principle, hybridize with the sample molecule of mark, by detecting the intensity of hybridization signal and distribution and then obtaining the sequence of target molecule and the information of quantity.The upholder of DNA chip comprises slide, silicon chip, NC film, Nylon film etc.DNA chip technology can be widely used in medical diagnosis on disease and treatment, farm crop good child-rearing preferably, judicial expertise, Food Hygiene Surveillance, many fields such as environment measuring.The detection technique of current DNA chip comprises fluorescence, mass spectrum and isotopic labeling, and wherein fluorescence is topmost detection method.Such as, but these having some limitations property of method: the spectral bands of fluorescence is wider, thus limit the Multiple detection to system; Different fluorescence dyes need the excitation of different-waveband, add testing cost; The phenomenon etc. of photobleaching is easily there is in fluorescence dye under the exciting of exciting light.
Surface enhanced Raman spectroscopy (SERS) technology is the Dynamic Non-Destruction Measurement of a kind of advanced person, it is that its Raman scattering signal is enhanced the phenomenon of multiple order of magnitude when molecular adsorption is at some Special Metal (being mainly precious metal) or nanometer semiconductor structure surface.SERS is the english abbreviation of Surface-enhanced Raman scattering, and Chinese meaning is surface enhanced Raman scattering.It has the advantage of quick, simple, highly sensitive, fingerprint recognition and favorable repeatability.SERS technology has obtained extensively, all plays more and more important effect in chemistry, biology and the field such as medical science and environment.Compared to fluorescence, SERS has abundant Raman spectrum line, and Raman spectrum bands of a spectrum are narrow, can provide more abundant structural information for analyte.Utilize now SERS in some systems, even can reach the detection sensitivity of single molecules level.But, also do not occur at present utilizing SERS technology and the gene chip designed.
Summary of the invention
The object of the invention is to utilize noble metal nano array and surface enhanced Raman spectroscopy (SERS) technology and design a kind of DNA chip, the determination and analysis of realize target DNA and gene.
The present invention is achieved by the following technical solutions: a kind of DNA chip, the SERS substrate that the substrate of this DNA chip is is substrate with noble metal nano array, SERS is the english abbreviation of Surface-enhanced Ramanscattering, and Chinese meaning is surface enhanced Raman scattering; Noble metal nano array divides and has some regions, the surface in each region is modified and is connected with different some DNA probes and makes DNA chip become chip containing different probe DNA, utilize these DNA probes to carry out detection to target dna and produce SERS signal, realize identification to target dna and detection by quantitative according to the change of frequency of SERS signal, amplitude difference.
As the further improvement of such scheme, a terminal modified sulfydryl of DNA probe, makes DNA probe and SERS substrate combine by sulfydryl.
As the further improvement of such scheme, described precious metal is golden Au or silver-colored Ag.
As the further improvement of such scheme, SERS substrate adopts the mode of plating or sputtering to be arranged in AAO template by noble metal nano array and is formed, AAO is the english abbreviation of Anodic Aluminum Oxide Template, and Chinese meaning is anodic oxidation aluminium formwork.
The present invention also provides the detection method of above-mentioned any DNA chip, and it comprises the following steps: in DNA chip, drip the solution containing target dna, make different DNA probes and target dna carry out complementary pairing and produce SERS signal; SERS signal on analyzing DNA chip: the detection by quantitative realizing the identification to target dna according to the change of frequency of SERS signal, amplitude difference.
As the further improvement of such scheme, it is further comprising the steps of: the reporter dna of a certain section of complementary pairing of further dropping or immersion and target dna in DNA chip, make one end of reporter dna with the molecular radical of SERS signal, then by the SERS signal on examining report DNA, the object of the detection and Identification to micro-target dna is reached.
The present invention also provides a kind of making method of DNA chip, the SERS substrate that the substrate of this DNA chip is is substrate with noble metal nano array; Noble metal nano array divides and has some regions, the surface in each region is modified and is connected with different some DNA probes, utilize these DNA probes to carry out detection to target dna and produce SERS signal, realize identification to target dna and detection by quantitative according to the change of frequency of SERS signal, amplitude difference.The making method of DNA chip comprises the following steps: 1) prepare the SERS substrate being substrate with noble metal nano array; 2) divide in noble metal nano array and have some regions, the surface in each region is modified and is connected with different some DNA probes and makes DNA chip and make DNA chip become chip containing different probe DNA.
As the further improvement of such scheme, a terminal modified sulfydryl of DNA probe, makes DNA probe and SERS substrate combine by sulfydryl.
As the further improvement of such scheme, the making of SERS substrate comprises: 1.1) preparation table wears the AAO template of nanotip structure tapered hole; 1.2) in AAO template, divide the grid of different zones, realize the preparation of Ag nano column array, form SERS substrate.
Further, SERS substrate is arranged in AAO template by the mode that the employing of noble metal nano array is electroplated or sputtered and is formed.
The present invention utilizes SERS technology, and designing with Precious Metals-Gold (Au) or silver (Ag) nano-array is the DNA chip of substrate.Choose or prepare noble metal nano array voluntarily, then different probe DNA is connected in the finishing of nano-array different zones, then these DNA probes are utilized to detect target dna according to the principle of DNA base pair complementarity, again according to actual needs, further dropping has the reporter dna of characteristic Raman signals, and realizes identification to target dna and detection by quantitative according to SERS signal (comprising frequency, the intensity) change on chip before and after DNA hybridization, difference.
Accompanying drawing explanation
The DNA detection principle schematic of the DNA chip that Fig. 1 provides for present pre-ferred embodiments.
The making of the DNA chip that Fig. 2 provides for present pre-ferred embodiments and testing process schematic diagram.
Fig. 3 is the tapered hole AAO Template preparation schema of DNA chip.
Fig. 4 is the preparation flow schematic diagram with the SERS substrate of reticulation Ag nano column array of DNA chip.
Spectrogram when Fig. 5 is the DNA probe direct-detection target dna utilizing DNA chip, concrete spectrum is: bottom is the SERS spectrum of DNA probe; Top is the SERS spectrum after DNA probe and different concns target dna are hybridized.
Fig. 6 be linking probe DNA in DNA chip SERS substrate on drip target dna to be measured, then detect the SERS signal graph with target dna Partial Fragment complementary pairing reporter dna, SERS signal is: bottom spectrum is that reporter dna directly tests the SERS signal obtained without any process; Top spectrum is the SERS signal of target dna under detection different concns.
Fig. 7 is for detecting target dna and the mixed SERS signal graph of reporter dna.
Embodiment
In order to make object of the present invention, technical scheme and advantage clearly understand, below in conjunction with embodiment, the present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
First the DNA declared in the present invention has three kinds: DNA probe, target dna and reporter dna.Wherein DNA probe is used for target acquisition DNA, and reporter dna is used for sending detectable signal.
DNA chip of the present invention, the SERS substrate that its substrate is is substrate with noble metal nano array; Noble metal nano array divides and has some regions, the surface in each region is modified and is connected with different some DNA probes and makes DNA chip become chip containing different probe DNA, utilize these DNA probes to carry out detection to target dna and produce SERS signal, realize identification to target dna and detection by quantitative according to the change of frequency of SERS signal, amplitude difference.
The ultimate principle of DNA chip of the present invention is as shown in Figure 1: choose or prepare noble metal nano array voluntarily, then different DNA probe is connected in the finishing of nano-array different zones, then these DNA probes are utilized to detect target dna according to the principle of DNA base pair complementarity, again according to actual needs, further dropping has the reporter dna of characteristic Raman signals, and (comprise frequency according to the SERS signal on chip before and after DNA hybridization, intensity) change, difference realizes identification to target dna and detection by quantitative, main finger change of frequency, amplitude difference.
As shown in Figure 2, the present invention utilizes business precious metal (Au or Ag) nano-array as the substrate of DNA chip, or, can oneself utilize AAO template method to prepare marshalling, spacing are suitable, the noble metal nano array of the active gold by force of SERS or silver as the substrate of DNA chip, wherein gold and silver nanometer display can be obtained by the method electroplated or sputter.Noble metal nano array divides sizeable zonule and (is labeled as 11 in the drawings, 12,13; 21,22,23 31,32,33 ...), different DNA probes can be connected on each zone, the mode that method of attachment can connect with sulfydryl, thus obtain
be suitable for SERS to survey amountdNA chip.
DNA chip drips the solution containing target dna, under suitable conditions (waiting time, temperature etc.), different DNA probes and corresponding target dna is made to carry out complementary pairing, then the SERS signal after hybridization is detected, and the change of the SERS signal (comprising frequency, intensity) of DNA on analysis chip, difference, tentatively judge the situation detecting target dna.
Can drip in DNA chip or soak and the reporter dna of target dna a certain section of complementary pairing, one end band has the molecular radical easily producing SERS signal, then by the SERS signal of examining report DNA, reaches the object of detection and Identification target dna.
The present invention is with the Ag nano column array obtained by the method for ion sputtering at tapered hole AAO template surface for SERS substrate, and prepared the DNA chip (original reason experiment) based on SERS technology, concrete steps are as follows:
1, surface is with the preparation of nanotip structure tapered hole AAO template
(1) once oxidation of AAO template: the high-purity aluminium flake after polishing is used in the oxalic acid solution of 0.3M 40V volts DS anodic oxidation 6h, then in the mixed solution of the 6wt ﹪ phosphoric acid of 60 DEG C and 1.8wt ﹪ chromic acid, 9h is soaked, to remove the pellumina in the irregular hole that first time anodic oxidation obtains on high-purity aluminium flake surface.
(2) surface is with the preparation of the AAO template of most advanced and sophisticated nanostructure: as shown in Figure 3, Fig. 3 is tapered hole AAO Template preparation schema to concrete preparation method.The method preparation table mask of cross-over oxidation reaming the aluminium substrate obtained in step (1) is utilized to have the alumina formwork of most advanced and sophisticated nanostructure.First aluminium substrate in the oxalic acid solution of 0.3M with 40V volts DS anodic oxidation 40s, then obtained template at 40 DEG C 5% phosphoric acid solution in reaming 2min, repeat alternately above-mentioned oxidation and reaming procedure 18 times.
2, the grid of different zones and the preparation of Ag nano column array is divided
As shown in Figure 4, Fig. 4 is the preparation flow schematic diagram of reticulation Ag nano column array DNA chip SERS substrate, and the template mainly comprised obtaining in 1 carries out photoetching treatment and ion sputtering two steps.
(1) photoetching treatment of AAO template
The tapered hole AAO template of preparation in 1 is placed on spin coating instrument, under the rotating speed of 4000 rpms, drips 2mL positive photoresist in template, spin coating photoresist material 20s.Then the baking oven that the AAO template of spun photoresist material is placed in 95 degrees Celsius is dried 15-20 minute.Then take out under template is placed in ultraviolet lamp and carry out exposure 36s, be then placed in developing solution and rinse, then clean with a large amount of deionized water.So just the AAO template of the surface in the reticulation region that we want with most advanced and sophisticated nanostructure is come out, and the template area around grid is also coated with photoresist material.
(2) preparation of the reticulation Ag nano column array of different zones is divided
Utilize EMITHCH K550 ion sputtering instrument at surface sputtering one deck Ag of AAO template, sputtering distance (vertical range between sample and target) is about 2cm, and sputtering current selects 20mA, and sputtering time is 16min.Ag particle aggregation, in the upper surface of " tapered hole " wall of the AAO template exposed, forms Ag " nano-pillar " array being positioned at the upper surface of " tapered hole " wall; The inwall of " tapered hole " simultaneously also obtain the more tiny nano particle of a large amount of diameter.And one deck Ag film can only be formed in the region being coated with photoresist material.
3, linking probe DNA makes DNA chip
The modifying method of DNA is selected at the terminal modified sulfydryl of DNA probe one, then by sulfydryl, DNA probe and SERS substrate is combined.Common practices is: the disulfide linkage that the dithiothreitol (DTT) (DTT) of the DNA probe 0.5M of sulfhydrylation or 0.1M (2-propyloic) phosphonium salt hydrochlorate (TCEP) solution-treated may be existed with minimizing, then uses NAP-5 chromatographic column to carry out purification process to DNA probe.Then the DNA probe after purifying is diluted to 5 and 15 μMs/L, then gets 10 μ L at every turn and drip on the Ag nano column array SERS substrate split, keep 12 hours under 5 DEG C of conditions.Then fall above Ag nano column array SERS substrate not combine firmly DNA probe by a large amount of washed with de-ionized water, then with high pure nitrogen, SERS substrate is dried up, the whether successful connection of inspection DNA probe can be measured by SERS.
4, in testing sample, the SERS of target dna detects
Connect multiple DNA probe compared to business-like biochip at multiple grid, we only have selected a kind of DNA probe, a kind of target dna and corresponding reporter dna and carry out original reason test in the present embodiment.This programme select target DNA is the DNA fragmentation of faecium, has statistics in the pathogenic bacterium causing urinary tract infections, and enterococcal infection occupies the 2nd; Abdominal cavity, pelvic infection, faecalis occupies the 3rd; Septicemia, faecalis occupies the 3rd, and case fatality rate reaches 12.6% ~ 57%; But at present for the treatment of the faecium specifics that also has nothing good, therefore this detection has very important practical significance.The probe used in this programme, target and reporter dna sequence are as shown in table 1.As shown in Figure 3, concrete operating process is as follows for DNA modification and complementary pairing schematic diagram:
The DNA sequence dna used in table 1 the present embodiment
(1) target dna is dissolved in containing 6 × SSPE (0.9M NaCl, 10mM NaH
2pO
4h
2o, 1mMEDTA, pH 7.4), in the mixing solutions of 20% (v/v) methane amide and 0.1% (w/v) SDS, then target dna is diluted to different concentration (0.1-2 μM/L), then SERS measurement is carried out to sample, record its SERS spectrum, as shown in Figure 5, Fig. 5 drips target dna on the chip of linking probe DNA, measures its SERS spectrum.Bottom is the SERS spectrum of the DNA probe of 5 μMs, and other are the SERS spectrum after DNA probe and different concns target dna are hybridized.
(2) reporter dna is dissolved in the phosphate buffered saline buffer containing 0.1% (w/v) SDS, and is diluted to 5 μMs/L.Utilize reporter dna, we have attempted measuring the SERS of target dna under following two kinds of conditions.
1) the first situation, the SERS substrate of linking probe DNA drips each 10 μ L (keeping 4h under 30 DEG C of conditions) of target dna solution of different concns, then a large amount of deionized water of SERS substrate is cleaned, then with high pure nitrogen, SERS substrate is dried up, and test its SERS signal; Then on the different SERS substrates after hybridization, the reporter dna solution (keeping 4h under 30 DEG C of conditions) that 10 μ L concentration are 5 μMs/L is respectively dripped, then with a large amount of deionized water, SERS substrate is rinsed, with high pure nitrogen, SERS substrate is dried up, and test its SERS signal, as shown in Figure 6, Fig. 6 drips target dna on the substrate of linking probe DNA, and then with the SERS signal of reporter dna complementary pairing.Bottom spectrum is that reporter dna directly tests the SERS signal obtained without any process, and other are the SERS signal detecting different concns target dna.
2) the second situation, first 5 μMs/L is put into reporter dna solution to mix with the target dna solution of different concns, and under 30 DEG C of conditions, keep 4h to make it carry out complementary pairing, then the DNA solution getting different concns after 10 μ L complementary pairings respectively drips and under 30 DEG C of conditions, keep 4h on the SERS substrate being connected with DNA probe, then with a large amount of deionized water, SERS substrate is rinsed, with high pure nitrogen, SERS substrate is dried up, and measure its SERS signal, as shown in Figure 7, the detection target dna of Fig. 7 and the mixed SERS signal of reporter dna, the concentration of target dna has been marked in figure.
(3) the SERS signal analysis of DNA
Ag nano column array SERS substrate be connected with DNA probe and with target dna complementary pairing after SERS spectrum as shown in Figure 6,7, wherein bottom is the SERS spectrum of the DNA probe of 5 μMs, and top is the SERS spectrum after DNA probe and different concns target dna are hybridized.Principal vibration peak 666cm on Raman spectrum
-1(belonging to the breathing vibration of guanine), 731cm
-1(belonging to the breathing vibration of VITAMIN B4), 790cm
-1(vibration peak of thymus pyrimidine and cytosine(Cyt)), 1323cm
-1(belonging to the vibration peak of single stranded DNA skeleton), 1469cm
-1(belonging to the vibration peak of VITAMIN B4 and single stranded DNA skeleton) is more remarkable.Investigate the ratio of their correspondences, analyze and find I (731cm
-1)/I (790cm
-1) and the concentration of detected target dna between linear numerical relation, as shown in Figure 6.Modify the DNA probe of 5 μMs at SERS substrate surface, the target dna of about 0.25 μM can be detected.By reducing the concentration of DNA probe, the limit of detection of target dna is expected to be reduced further.
In order to improve to target dna detect specificity and sensitivity, further operation report DNA, by the signal of Raman dye molecule above examining report DNA.As shown in Figure 6 and Figure 7, the reporter dna after complementary pairing is consistent with the main peaks of the reporter dna directly surveyed, and still has better SERS signal when the concentration of target dna is low to moderate 0.1 μM for the SERS signal dripped or soaked reporter dna.
We also tested simultaneously and first reporter dna mixed with target dna, and then with the SERS signal of DNA probe complementary pairing.We find that the SERS signal detection limit of reporter dna in this case increases, and still have better SERS signal when the concentration of reporter dna is low to moderate 0.1 μM.In addition, in the target dna that in experimenting, we find out that is immersed in different concns substrate and reporter dna solution, due to detected molecule number increase therefore limit of detection also can improve accordingly.
Above content is in conjunction with the detailed description made for the present invention of concrete accompanying drawing, can not assert that the present invention specifically implements to be only limitted to these explanations.For those skilled in the art, without departing from the inventive concept of the premise, some simple replacements and change can also be made, all should be considered as belonging to the invention protection domain that the present invention is determined by submitted to claims.
Claims (10)
1. a DNA chip, is characterized in that: the SERS substrate that the substrate of this DNA chip is is substrate with noble metal nano array, and SERS is the english abbreviation of Surface-enhanced Raman scattering, and Chinese meaning is surface enhanced Raman scattering; Noble metal nano array divides and has some regions, the surface in each region is modified and is connected with different some DNA probes and makes DNA chip become chip containing different probe DNA, utilize these DNA probes to carry out detection to target dna and produce SERS signal, realize identification to target dna and detection by quantitative according to the change of frequency of SERS signal, amplitude difference.
2. DNA chip according to claim 1, is characterized in that: a terminal modified sulfydryl of DNA probe, by sulfydryl, DNA probe and SERS substrate is combined.
3. DNA chip according to claim 1, is characterized in that: described precious metal is golden Au or silver-colored Ag.
4. DNA chip according to claim 1, it is characterized in that: SERS substrate adopts the mode of plating or sputtering to be arranged in AAO template by noble metal nano array and formed, AAO is the english abbreviation of AnodicAluminum Oxide Template, and Chinese meaning is anodic oxidation aluminium formwork.
5. a detection method for DNA chip as claimed in any of claims 1 to 4, is characterized in that: it comprises the following steps:
DNA chip drips the solution containing target dna, makes different DNA probes and target dna carry out complementary pairing and produce SERS signal;
SERS signal on analyzing DNA chip: the detection by quantitative realizing the identification to target dna according to the change of frequency of SERS signal, amplitude difference.
6. the detection method of DNA chip according to claim 5, it is characterized in that: it is further comprising the steps of: the reporter dna of a certain section of complementary pairing of further dropping or immersion and target dna in DNA chip, make one end of reporter dna with the molecular radical of SERS signal, then by the SERS signal on examining report DNA, the object of the detection and Identification to micro-target dna is reached.
7. a making method for DNA chip according to claim 1, is characterized in that: it comprises the following steps:
1) the SERS substrate being substrate with noble metal nano array is prepared;
2) divide in noble metal nano array and have some regions, the surface in each region is modified and is connected with different some DNA probes and makes DNA chip and make DNA chip become chip containing different probe DNA.
8. the making method of DNA chip according to claim 7, is characterized in that: a terminal modified sulfydryl of DNA probe, by sulfydryl, DNA probe and SERS substrate is combined.
9. the making method of DNA chip according to claim 7, is characterized in that: the making of SERS substrate comprises:
1.1) preparation table wears the AAO template of nanotip structure tapered hole;
1.2) in AAO template, divide the grid of different zones, realize the preparation of Ag nano column array, form SERS substrate.
10. the making method of DNA chip according to claim 9, is characterized in that: SERS substrate adopts the mode of plating or sputtering to be arranged in AAO template by noble metal nano array and formed.
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| CN108444541A (en) * | 2018-06-05 | 2018-08-24 | 天津大学 | The environment network of silver ion content is detected based on aldehyde radical chip and gold nano grain |
| CN108444546A (en) * | 2018-06-05 | 2018-08-24 | 天津大学 | The environment network of silver ion content is detected based on genetic chip and silver nano-grain |
| CN108444542A (en) * | 2018-06-05 | 2018-08-24 | 天津大学 | The environment network of silver ion content is detected based on gold silver nanometer particle |
| CN108444545A (en) * | 2018-06-05 | 2018-08-24 | 天津大学 | The environment network of silver ion content is detected based on aldehyde radical chip and silver nano-grain |
| CN108444547A (en) * | 2018-06-05 | 2018-08-24 | 天津大学 | The environment network of mercury ion content is detected based on genetic chip and silver nano-grain |
| CN108444538A (en) * | 2018-06-05 | 2018-08-24 | 天津大学 | The environment network of mercury ion content is detected based on aldehyde radical chip and gold nano grain |
| CN108444544A (en) * | 2018-06-05 | 2018-08-24 | 天津大学 | The environment network of mercury ion content is detected based on silver nano-grain |
| CN108444539A (en) * | 2018-06-05 | 2018-08-24 | 天津大学 | The environment network of silver ion content is detected based on silver nano-grain |
| CN108444548A (en) * | 2018-06-05 | 2018-08-24 | 天津大学 | The environment network of mercury ion content is detected based on gold nano grain |
| CN108444543A (en) * | 2018-06-05 | 2018-08-24 | 天津大学 | The environment network of mercury ion content is detected based on gold silver nanometer particle |
| CN108507623A (en) * | 2018-06-05 | 2018-09-07 | 天津大学 | The environment network of silver ion content is detected based on gold nano grain |
| CN108507624A (en) * | 2018-06-05 | 2018-09-07 | 天津大学 | The environment network of silver ion content is detected based on genetic chip and gold nano grain |
| CN108519128A (en) * | 2018-06-05 | 2018-09-11 | 天津大学 | The environment network of mercury ion content is detected based on genetic chip and gold nano grain |
| CN108444540A (en) * | 2018-06-05 | 2018-08-24 | 天津大学 | The environment network of mercury ion content is detected based on aldehyde radical chip and silver nano-grain |
| US11149298B2 (en) | 2018-06-13 | 2021-10-19 | International Business Machines Corporation | Detection of nucleic acid sequences using deterministic lateral displacement arrays |
| US11180796B2 (en) | 2018-06-13 | 2021-11-23 | International Business Machines Corporation | Detection of mutations regarding one or more deoxyribonucleic acid sequences using deterministic lateral displacement arrays |
| CN109900676A (en) * | 2019-03-21 | 2019-06-18 | 中国科学院合肥物质科学研究院 | A method of using the detection radiation damage of SERS substrate |
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