CN212189150U - Micro-fluidic chip for solving minimum set coverage problem - Google Patents
Micro-fluidic chip for solving minimum set coverage problem Download PDFInfo
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- CN212189150U CN212189150U CN202020456640.4U CN202020456640U CN212189150U CN 212189150 U CN212189150 U CN 212189150U CN 202020456640 U CN202020456640 U CN 202020456640U CN 212189150 U CN212189150 U CN 212189150U
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Abstract
The utility model discloses a micro-fluidic chip for solving the problem of minimum set coverage in the technical field of biological computers, which comprises a sample adding hole, a sample adding channel, a substrate liquid pool, a reaction pool group, a waste liquid pool, a liquid outlet channel, a capillary channel, a first micro-fluid channel and a second micro-fluid channel, and the chip has simple structure and convenient manufacture and does not need to integrate elements such as any micro-valve micropump; the flow of the solution on the chip is driven by centrifugal force, all possible results can be exhausted on the chip, whether the results meet the conditions or not can be verified at the same time, the DNA sequence does not need to be repeatedly added on the chip, manual intervention is reduced, the problems of large serial calculation amount and large time complexity in the traditional algorithm are solved, the powerful parallel capability of DNA calculation is realized, the MSC problem is solved by using the reaction of DNAzyme cracking RNA on the chip, and the calculation reliability is effectively improved.
Description
Technical Field
The utility model relates to a biological computer technical field specifically is a solve micro-fluidic chip of minimum set coverage problem.
Background
The minimum set coverage problem (MSC) is an important NP complete problem, and has wide application in the fields of planning and scheduling, order distribution, information retrieval, network facility site selection, vehicle path optimization, and the like. Researchers have proposed a variety of algorithms to solve this problem, such as greedy algorithms, approximation algorithms, genetic algorithms, artificial bee colony algorithms, and the like. However, these algorithms have a high time complexity and a low timeliness, and cannot perform parallel computation. DNA computing, a new molecular computing model, can be used to solve various NP problems due to its high degree of parallel computing power, mass storage capability, excellent search strategy, and ultra-fast computing speed. DNAzymes are a class of artificially synthesized DNA molecules with catalytic activity that cleave specific substrates in the presence of cofactors. Because of its good programming ability, stability and activity, relatively cheap synthesis, easy modification and functionalization, it has been widely used in the fields of analytical applications, biosensors, chemical biology and nanotechnology. Generally, such dnazymes are composed of a substrate chain and an enzyme chain. The substrate strand contains a single-stranded RNA junction (rA) as cleavage site, while the enzyme chain consists of a catalytic core and two arms. In the presence of catalytic cofactors (which may be different metal ions and amino acids), the enzyme chain cleaves the substrate strand into two parts. According to the characteristic of DNAzyme, the MSC problem is converted into DNAzyme cracking reaction on a microfluidic chip, and a promising thought is provided for the application of DNAzyme in the field of intelligent computing.
The Microfluidic chip technology is a technology that basic operation units such as sample preparation, reaction, separation, detection and the like are integrated on a micron-scale chip to automatically complete the whole process of analysis, detection, operation and the like. The development of the technology provides a powerful technical support and platform for solving the problems of complex operation process, more required containers, large sample consumption, low reaction efficiency, serious pollution and the like in the traditional biochemical reaction. To realize the operation or detection function of the microfluidic chip, driving and controlling the flow of liquid in the chip become the key problems of the technology. The traditional driving mode is electroosmosis driving and pressure driving, the electroosmosis driving needs high-voltage power supply equipment, and a driving system is complex and large; the latter includes two kinds, one is coupling with microfluid pipeline by using macroscopic pump or injector, and the method is simple, easy to implement and low in cost, but not easy to miniaturize, and the other is using micromachining to make micropump to provide power, and its process is complex and cost is high. Centrifugal force driving is a unique technology in the microfluidic technology, and the centrifugal force generated when a chip is driven by a micro motor to do circular motion is used as the driving force of liquid. Because centrifugal micro-fluidic chip has the characteristics of processing convenience, drive simple, do not need extra pump and valve, can realize complicated biochemical reaction process on a chip, consequently become the research and the application focus in micro-fluidic chip field, it is the present important research task to combine together DNAzyme technique and micro-fluidic technique and be used for solving the MSC problem, so need a new-type micro-fluidic chip urgently, based on this, the utility model designs a solve the micro-fluidic chip of minimum set coverage problem to solve above-mentioned problem.
SUMMERY OF THE UTILITY MODEL
An object of the utility model is to provide a solve the micro-fluidic chip of minimum set coverage problem to solve the problem that proposes among the above-mentioned background art.
In order to achieve the above object, the utility model provides a following technical scheme: the utility model provides a solve micro-fluidic chip of minimum set coverage problem, includes application of sample hole, application of sample passageway, substrate liquid pool, reaction tank group, waste liquid pool, play fluid channel, capillary channel, first micro-fluidic channel and second micro-fluidic channel, application of sample passageway intercommunication application of sample hole and substrate liquid pool, first micro-fluidic channel intercommunication substrate liquid pool and reaction tank group, capillary channel intercommunication reaction tank group and waste liquid pool, second micro-fluidic channel intercommunication waste liquid pool and play fluid channel.
Further, the reaction tank group comprises five reaction tanks which are numbered from a to e in sequence.
Furthermore, a substrate layer is arranged among the microfluidic chip modules which are composed of the sample adding hole, the sample adding channel, the substrate liquid pool, the reaction pool group, the waste liquid pool, the capillary channel, the first microfluidic channel and the second microfluidic channel.
Furthermore, the basal layer is circular and a circular liquid outlet channel is arranged on the outer side of the surface of the basal layer.
Furthermore, eight groups of micro-fluidic chip modules are uniformly arranged on the surface of the substrate layer in a circular shape at intervals, and second micro-fluidic channels of the eight groups of micro-fluidic chip modules are communicated with the liquid outlet channel.
Compared with the prior art, the beneficial effects of the utility model are that: the chip of the utility model has simple structure and convenient manufacture, and does not need to integrate any micro-valve micro-pump and other elements; the flow of the solution on the chip is driven by centrifugal force, all possible results can be exhausted on the chip, whether the results meet the conditions or not can be verified at the same time, the DNA sequence does not need to be repeatedly added on the chip, manual intervention is reduced, the problems of large serial calculation amount and large time complexity in the traditional use are solved, the powerful parallel capability of DNA calculation is realized, the MSC problem is solved by using the DNAzyme cracking RNA reaction on the chip, and the calculation reliability is effectively improved.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to these drawings without creative efforts.
Fig. 1 is a schematic structural diagram of an operation system of a microfluidic operation chip provided by the present invention;
FIG. 2 is a schematic diagram of DNAzyme cleavage of mRNA provided by the present invention;
FIG. 3 is a schematic diagram of the structure of a DNAzyme sequence used in the present invention;
fig. 4 is a perspective view of the chip structure of the present invention.
In the drawings, the components represented by the respective reference numerals are listed below:
a sample adding hole 1, a sample adding channel 2, a substrate liquid pool 3, a reaction pool group 4, a waste liquid pool 5, a liquid outlet channel 6, a capillary channel 7, a first microfluid channel 8 and a second microfluid channel 9.
Detailed Description
The technical solutions in the embodiments of the present invention will be described clearly and completely with reference to the accompanying drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by a person of ordinary skill in the art without creative efforts belong to the protection scope of the present invention.
In the description of the present invention, it is to be understood that the terms "upper", "lower", "front", "rear", "left", "right", "top", "bottom", "inner", "outer", and the like indicate orientations or positional relationships based on the orientations or positional relationships shown in the drawings, and are only for convenience of description and simplicity of description, and do not indicate or imply that the device or element being referred to must have a particular orientation, be constructed and operated in a particular orientation, and therefore, should not be construed as limiting the present invention.
Referring to fig. 1-4, the present invention provides a technical solution: the utility model provides a solve micro-fluidic chip of minimum set coverage problem, includes application of sample hole 1, application of sample passageway 2, substrate liquid pool 3, reaction cell group 4, waste liquid pond 5, drain channel 6, capillary channel 7, first micro-fluidic channel 8 and second micro-fluidic channel 9, application of sample passageway 2 intercommunication application of sample hole 1 and substrate liquid pool 3, first micro-fluidic channel 8 intercommunication substrate liquid pool 3 and reaction cell group 4, capillary channel 7 intercommunication reaction cell group 4 and waste liquid pond 5, second micro-fluidic channel 9 intercommunication waste liquid pond 5 and drain channel 6.
The reaction tank group 4 comprises five reaction tanks which are numbered a-e in sequence, a basal layer is arranged between microfluidic chip modules which are composed of a sample adding hole 1, a sample adding channel 2, a substrate liquid tank 3, the reaction tank group 4, a waste liquid tank 5, a capillary channel 7, a first microfluidic channel 8 and a second microfluidic channel 9, the basal layer is circular, a circular liquid outlet channel 6 is arranged on the outer side of the surface of the basal layer, eight groups of microfluidic chip modules are uniformly arranged on the surface of the basal layer at intervals in a circular shape, and the second microfluidic channels 9 of the eight groups of microfluidic chip modules are communicated with the liquid outlet channel 6.
The working principle is as follows:
FIG. 2 illustrates the principle of DNAzyme cleavage of mRNA, where the mRNA sequence is ligated (rA) as the cleavage site and the DNAzyme sequence consists of a catalytic core and two arms, and the DNAzyme will be directed to a specific cleavage site by designing the binding arms using the Watson-Crick base complementary pairing principle; DNAzymes cleave mRNA sequences into two parts in the presence of catalytic cofactors, binding fluorescent groups (e.g., FAM) and quenching groups (e.g., IABKFQ) at both ends of the mRNA sequences, and the cleavage reaction of mRNA is easily detected by these fluorescent signals, which can be used to reflect the computational results of many problems.
S was expressed using a sodium-specific DNAzyme (NaA43)iThe corresponding mRNA sequence is shown as
The DNAzyme can specifically and rapidly recognize and crack the characteristic site (rA) of the mRNA sequence in the presence of Na +; to obtain a detectable signal, a quencher was labeled at the 3' end of the DNAzyme strand, and a fluorophore and a quencher were labeled at the 5' and 3' ends of the mRNA strand, respectively, as shown in FIG. 3.
The DNAzyme sequences and mRNA sequences were encoded according to the principle of DNAzyme cleavage of mRNA, as shown in Table 1, where SiShowing the sequence of a DNAzyme,
represents the corresponding mRNA sequence; each SiThe middle part of (A) is encoded as NaA43A catalytic core, corresponding
The middle part of (a) encodes a TrAGGAA sequence which can be cleaved by its specific recognition, in order to distinguish the individual SiElements, the base sequences at both ends may be different sequences as long as they are ensured
And SiAnd (3) base complementation.
Table 1: RNA and DNAzyme encoding
The DNA calculation method of the microfluidic chip for solving the minimum set coverage problem comprises the following steps:
s1: designing a chip and numbering each repeating unit of the chip, designing a corresponding centrifugal microfluidic chip model according to the minimum set coverage problem, wherein the set C has q elements, so that the total number is 2qSeed combinations, and the set S has p elements, so the chip has 2qIndependent repeating units, each unit containing p reaction cells, sequentially mixing 2qUnit according to C1,C2,...CqThe values in different combinations are numbered and marked, e.g. number 0 indicates C1＝C2＝...＝CqNo. 3 represents C as 01～CqC in1＝C 21, all other elements are 0, and as shown in table 2, reaction cells d of each independent repeating unit are also numbered from 1 to p;
table 2: mark number
S2: coding the required sequence and initializing the calculation template, designing DNAzyme required by coding customization according to the algorithm principle andRNA sequence, mRNA sequence solution representing each element in the set S and Na + required for the reaction are sequentially added to each of the reaction cells d (a to e) of each repeating unit, and the solution is sequentially added to 2 through the wells in accordance with the number in step S1qIn the substrate bath of the repeating units according to C1～CqAdding the DNAzyme sequence solution corresponding to the elements contained in the DNAzyme sequence solution into the values of different combinations according to the following rules: if CiIf the value is 1, C is addediThe DNAzyme sequence solution corresponding to the element contained in (A) if (C)iIf the value is 0, no corresponding DNAzyme sequence is added, and if no reagent is added to the substrate liquid pool with the number of 0; addition of C alone to the substrate bath numbered 11DNAzyme sequence solution corresponding to the elements contained in the DNA sequence solution; is numbered as 2q-1 pool addition of substrate C1～CqDNAzyme sequence solution corresponding to the elements contained in the DNA sequence solution;
s3: fixing the chip on a centrifuge, starting the centrifuge, driving DNAzyme sequence solutions of each substrate liquid pool to respectively enter corresponding reaction pools by controlling the centrifugal force, if an mRNA sequence complementary with a base of the DNAzyme sequence entering the reaction pools can be found, quickly and specifically identifying and cutting a specific site (rA) of the RNA sequence, and dissociating a fluorescent group and a quenching group in the solution to release fluorescence due to the cleavage of the mRNA; observing results and recording feasible solutions: observing the fluorescence condition in the reaction cell d of each repeating unit in the chip by using a laser confocal microscope and recording, wherein the recording rule is as follows: recording the fluorescence emitted in the reaction cell d as 1 and recording the non-fluorescence as 0; counting the recording condition of each repeating unit, wherein all 1 is a feasible solution of the problem, and recording the unit number corresponding to the feasible solution; and (3) selecting an optimal solution from the feasible solutions: counting the corresponding C in the feasible solution1～CqThe number of the median value is 1, and the solution with the minimum number is used as the solution of the minimum set coverage problem.
The utility model discloses combine DNAzyme technique and micro-fluidic technique, a centrifugal micro-fluidic chip model is used for solving the MSC problem is proposed, and the concrete structure and the biological operation algorithm of chip model have been given, this model is through the structure of designing a plurality of repetitive units on centrifugal micro-fluidic chip, utilize DNAzyme schizolysis mRNA's on the chip reaction to solve the MSC problem, the problem that time complexity is big among the traditional algorithm, serial calculation volume is big has been solved, realize the powerful parallel ability of DNA calculation; the flow of the solution on the chip is driven by centrifugal force, so that manual intervention is reduced, the algorithm process is simple, and operations of combining, separating, setting, clearing and reagent adding do not need to be repeated; and benefiting from the rapid development of the micromachining technology, the chip integrating a plurality of repeating units has small size, simple structure and low manufacturing cost, can effectively reduce the volume of a sample solution, reduce reaction time, remarkably improve the calculation reliability and provide a new idea for solving the minimum set coverage problem.
Examples
With S ═ S1,S2,S3,S4,S5}，C＝{C1,C2,C3,C4}，C1＝{S1,S3,S4,S5}， C2＝{S1,S4}，C3＝{S2,S5}，C4＝{S2,S3,S4For example, since the set C has 4 elements, i.e. 16 repeated units are needed, two chips as shown in fig. 1 can be used to solve the MSC problem, and the specific process is as follows:
(1) designing chip and making numbering mark, designing 2 chips as shown in FIG. 4, sequentially arranging 16 units according to C1,C2,...C4The values in the different combinations are numbered and labeled as shown in table 3;
table 3: unit numbering
(2) Encoding DNAzyme and RNA sequences required for synthesis, mRNA sequence solutions representing the elements of set S and N required for reaction were added to the reaction cells d (a to e) of each repeating unit in sequence, respectivelya +; and sequentially placing the substrate liquid pool C with 16 repeating units according to the number in the table 3 as per C1～C4Adding DNAzyme sequence solutions corresponding to the elements contained in the DNAzyme sequence solutions to values in different combinations, wherein the adding conditions are shown in Table 5;
table 4: DNAzymes and mRNA encodings in the present application examples
Table 5: addition of DNAzyme sequences in this application example
(3) Fixing the chip on a centrifuge, driving the DNAzyme sequence solutions of each substrate solution pool to enter the corresponding reaction pools respectively, observing results and recording feasible solutions as shown in Table 6, wherein the feasible solutions marked in the Table 6 are the feasible solutions of the minimum set coverage problem, and selecting the optimal solution from the feasible solutions: counting the corresponding C in the possible solution1～C4The number of values taken as 1, the least of which is the solution to the minimum binding coverage problem, as shown in table 7; therefore, solution of the minimum join coverage problem { C1,C4And { C }1,C3}。
Table 6: calculation results
Table 7: optimal solution statistics
In the description herein, references to the description of "one embodiment," "an example," "a specific example," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
The preferred embodiments of the present invention disclosed above are intended only to help illustrate the present invention. The preferred embodiments are not intended to be exhaustive or to limit the invention to the precise embodiments disclosed. Obviously, many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the invention and its practical applications, to thereby enable others skilled in the art to best understand the invention for and utilize the invention. The present invention is limited only by the claims and their full scope and equivalents.
Claims (5)
1. A microfluidic chip for solving a minimum set coverage problem, comprising: including application of sample hole (1), application of sample passageway (2), substrate liquid pool (3), reaction pool group (4), waste liquid pool (5), play liquid channel (6), capillary channel (7), first microfluidic channel (8) and second microfluidic channel (9), application of sample passageway (2) intercommunication application of sample hole (1) and substrate liquid pool (3), first microfluidic channel (8) intercommunication substrate liquid pool (3) and reaction pool group (4), capillary channel (7) intercommunication reaction pool group (4) and waste liquid pool (5), second microfluidic channel (9) intercommunication waste liquid pool (5) and play liquid channel (6).
2. The microfluidic chip for solving the problem of minimum set coverage according to claim 1, wherein: the reaction tank group (4) comprises five reaction tanks which are numbered a to e in sequence.
3. The microfluidic chip for solving the problem of minimum set coverage according to claim 1, wherein: and a basal layer is arranged between the microfluidic chip modules consisting of the sample adding hole (1), the sample adding channel (2), the substrate liquid pool (3), the reaction pool group (4), the waste liquid pool (5), the capillary channel (7), the first microfluidic channel (8) and the second microfluidic channel (9).
4. A microfluidic chip for solving the problem of minimum set coverage according to claim 3, wherein: the basal layer is circular and a circular liquid outlet channel (6) is arranged on the outer side of the surface of the basal layer.
5. A microfluidic chip for solving the problem of minimum set coverage according to claim 3, wherein: eight groups of micro-fluidic chip modules are uniformly arranged on the surface of the substrate layer in a circular shape at intervals, and second micro-fluidic channels (9) of the eight groups of micro-fluidic chip modules are communicated with the liquid outlet channel (6).
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| CN111420718A (en) * | 2020-04-01 | 2020-07-17 | 安徽大学 | Microfluidic chip for solving minimum set coverage problem and DNA (deoxyribonucleic acid) calculation method thereof |
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