CN117797888A

CN117797888A - Capillary array integrated plate for microfluidic mixing equipment

Info

Publication number: CN117797888A
Application number: CN202410085925.4A
Authority: CN
Inventors: 请求不公布姓名
Original assignee: Chengdu Westin Biomedical Technology Co ltd
Current assignee: Chengdu Westin Biomedical Technology Co ltd
Priority date: 2024-01-22
Filing date: 2024-01-22
Publication date: 2024-04-02

Abstract

The invention belongs to the field of biological medicine, and particularly relates to a capillary array integrated plate for microfluidic mixing equipment and a multichannel base matched with the capillary array integrated plate. The capillary array collecting plate comprises a collecting plate and capillaries connected with the collecting plate; one end of the capillary tube is connected with the collecting plate, and the inner cavity of the capillary tube penetrates through the collecting plate; the multichannel base comprises a mixing channel and a sample injection channel; the sample injection channel is communicated with the mixing channel. The capillary array integrated plate disclosed by the invention is used for mixing microfluidic multiphase solution together with a multi-channel base for matching, and lipid nano particles with excellent particle size, PDI and encapsulation efficiency can be prepared when the total mixing flow rate is 50-600 mL/min; compared with the prior micro-fluidic technology, the method has remarkable and excellent effect in preparing the sample at a high flow rate and linearly amplifying.

Description

Capillary array integrated plate for microfluidic mixing equipment

Technical Field

The invention belongs to the field of biological medicine, and relates to a capillary array integrated plate for microfluidic mixing equipment.

Background

Microfluidic (Microfluidics) refers to the science and technology involved in the handling or manipulation of tiny fluids using microchannels, an emerging interdiscipline involving chemical, fluid physics, microelectronics, biology and biomedical engineering. The core structure of the microfluidic mixing device of the invention generally adopts two sample injection channel pipelines, two solutions are conveyed to the core structure of the microfluidic mixing part according to a certain proportion for mixing, the core structure of the microfluidic mixing part can be designed into different flow channel structures, so that the flowing liquid can be mixed in a turbulent flow, laminar flow or collision mode, chemical micro-reaction is realized, or nano preparations such as preparations with particle diameters of nanometer and micrometer grade, such as liposome, lipid nanoparticle, core-shell nanoparticle, PLGA nanoparticle, micelle, nanoemulsion and the like are prepared.

In the prior art, the mixing of different fluids in a core structure of a microfluidic mixing part is generally realized by free diffusion or turbulent mixing which occurs when a liquid flows through a flow channel with a variable cross section or a multi-angle bending. The efficiency of free diffusion or turbulent mixing is positively correlated to the specific surface area of contact between the mixed solutions. Because the micro-mixing structure of the micro-flow control has smaller size and limited length, when the micro-flow control is adopted for mixing, two phases or even multiphase liquid need to be uniformly mixed in a shorter time so as to obtain nano particles and a compound thereof with uniform particle size and high encapsulation rate. Therefore, in the design of the microfluidic mixed structure, in order to increase the contact specific surface area between different fluids, the flow channel diameter of the microfluidic mixed structure is usually in the micron level, and good mixing is realized through the optimal design of the mixed flow channel structure, so that the preparation of small sample can be completed in the mode, but the requirements of mass sample preparation or industrialized sample production cannot be met due to the smaller flow channel diameter and limited flux of the flow channel. When the mixing structure is unchanged and the diameter of the channel is simply increased, the specific contact surface area between the liquids is low, so that the mixing efficiency is low, and the complete mixing of the two-phase or multi-phase solution cannot be realized. This is why current microfluidic mixing devices cannot be scaled up from a small scale structure linearization to pilot scale and even industrial devices. Therefore, the existing microfluidic mixed structure and the optimization thereof are only suitable for micro-reaction synthesis or nano preparation on a laboratory scale, and still cannot meet the requirement of large-scale production; the problems of mixed structure blockage, fluid pressure rise, mixing efficiency reduction and the like, which are unavoidable when the existing microfluidic device is amplified in large-scale production, lead to the damage of the mixed structure, the particle size and the particle size distribution of the prepared nano preparation become large, the encapsulation rate or the drug loading rate is reduced, even the phenomena of nano particle sedimentation, agglomeration and the like occur, and the requirements of industrial amplified production cannot be met.

Disclosure of Invention

Based on the technical defect that the existing microfluidic mixing equipment is only suitable for micro-reaction synthesis or nano preparation on a laboratory scale, can not realize linearization amplification and is not beneficial to industrial expansion production and application.

The first aspect of the invention provides a capillary array integrated board for microfluidic mixing equipment; comprises a collecting plate and a capillary connected with the collecting plate; one end of the capillary tube is connected to the collecting plate, and the inner cavity of the capillary tube penetrates through the collecting plate;

further, the capillary array is arranged in one or more of circular arrangement, square arrangement, elliptic arrangement, triangular arrangement, hexagonal arrangement, pentagonal arrangement, trapezoidal arrangement, star arrangement or random arrangement;

further, the number of the capillaries is 2-100;

further, the outer diameter of the capillary tube is 0.05 mm-10 mm;

further, the inner diameter of the capillary tube is 0.01-5 mm;

further, the integrated plate is one of a cylinder, an elliptic cylinder, a square cylinder, a trapezoid cylinder, a hexagonal cylinder, a pentagonal cylinder, a triangular cylinder and a star-shaped cylinder;

further, the integrated plate is cylindrical; the diameter of the circle is 1-100 mm;

further, the number of the capillaries is preferably 7 to 50; most preferably 7 to 31;

further, the length of the capillary tube is 10-100 mm; preferably 15-21 mm;

in a specific embodiment of the invention, the number of the capillaries is 7;

in another embodiment of the present invention, the number of capillaries is 13;

in another embodiment of the present invention, the number of capillaries is 19;

in another embodiment of the present invention, the number of capillaries is 31;

in a specific embodiment of the invention, the length of the capillary tube is 15mm;

in another embodiment of the invention, the length of the capillary tube is 21mm;

in a specific embodiment of the invention, the capillary has an outer diameter of 0.3mm;

in another embodiment of the invention, the capillary has an outer diameter of 0.5mm;

in a specific embodiment of the invention, the capillary has an inner diameter of 0.1mm;

in another embodiment of the invention, the capillary tube has an inner diameter of 0.2mm;

in another embodiment of the invention, the capillary tube has an inner diameter of 0.3mm;

in a specific embodiment of the invention, the collector plate is cylindrical; the diameter of the circle is 8mm;

the second aspect of the invention provides a multi-channel base used in cooperation with the capillary array collecting plate of the first aspect, comprising a mixing channel and a sample injection channel; the sample injection channel is communicated with the mixing channel; the sample injection channel comprises a left sample injection channel and a right sample injection channel;

further, the matched capillary tubes of the capillary array integrated plate extend into the mixing channel;

further, the upper side surface of the base comprises an upper sample injection groove, the left side surface and the right side surface of the base respectively comprise a left sample injection groove and a right sample injection groove, and the lower side surface of the base comprises a mixed sample outlet groove; the upper sample feeding groove is communicated with the mixed sample discharging groove through a mixing channel; the left sample injection groove and the right sample injection groove are communicated with the mixing channel through a left sample injection channel and a right sample injection channel respectively;

further, the size of the upper sample injection groove is not smaller than the size of a collecting plate of the capillary array collecting plate;

further, the mixing channel is square, polygonal and cylindrical; preferably cylindrical;

further, the length of the mixing channel is 10-1000 mm;

further, the diameter of the mixing channel is 1-100 mm;

further, the left sample injection channel and the right sample injection channel are cylindrical;

further, the diameters of the left sample injection channel and the right sample injection channel are 1-20 mm;

further, the distances between the left sample injection channel, the right sample injection channel and the upper sample injection groove are smaller than the length of the capillary tube;

in a specific embodiment of the present invention, the upper sample injection groove is circular;

in the specific embodiment of the invention, the left sample injection groove, the right sample injection groove and the mixed sample outlet groove are round;

the invention has the beneficial effects that:

according to the capillary array integrated plate for the microfluidic mixing equipment, a plurality of capillaries are arranged on the integrated plate in an array mode, then, the mixed solution A to be mixed and the mixed solution B to be mixed in a microfluidic mode are mixed together with a multi-channel base matched with the capillary array integrated plate, and lipid nano particles with excellent particle size, PDI and encapsulation efficiency can be prepared when the total flow rate of mixing is 50-600 mL/min; compared with the prior micro-fluidic technology, the method has remarkable and excellent effect in preparing the sample at a high flow rate and linearly amplifying.

Drawings

FIG. 1 is a schematic front view of a capillary array manifold structure of the present invention;

FIG. 2 is a schematic top view of a capillary array manifold structure of the present invention;

FIG. 3 is a schematic bottom view of a capillary array manifold structure according to the present invention;

FIG. 4 is a schematic view in partial cross-section of a front view of a capillary array collection sheet structure of the present invention;

FIG. 5 is a schematic illustration of one embodiment of a capillary array integrated plate of the present invention;

FIG. 6 is a schematic illustration of another embodiment of a capillary array manifold plate according to the present invention;

FIG. 7 is a schematic illustration of another embodiment of a capillary array manifold plate according to the present invention;

FIG. 8 is a schematic illustration of another embodiment of a capillary array manifold plate according to the present invention;

FIG. 9 is a schematic illustration of another embodiment of a capillary array manifold plate according to the present invention;

FIG. 10 is a schematic illustration of another embodiment of a capillary array manifold plate according to the present invention;

FIG. 11 is a schematic cross-sectional front view of a capillary array manifold and multi-channel mount of the present invention;

FIG. 12 is a schematic left-hand view of a multi-channel mount cooperating with a capillary array manifold of the present invention;

FIG. 13 is a schematic top view of a multi-channel mount mated with a capillary array manifold of the present invention;

FIG. 14 is a schematic view of a capillary array manifold of the present invention in use with a multi-channel mount;

FIG. 15 is a schematic diagram of a commercially available Michael chip;

in the figure, 1, a collecting plate; 2. a capillary tube; 3. an inner cavity; 4. a multi-channel base; 5. a mixing channel; 6. an upper sample injection groove; 7. a left sample introduction groove; 8. a right sample introduction groove; 9. mixing and discharging the sample groove; 10. a left sample injection channel; 11. a right sample injection channel; 12. the capillary array collecting plate is placed in the direction of the multi-channel base; 13. the liquid inlet schematic direction of the solution A to be mixed; 14. mixing and outputting a sample schematic direction; 15. the sample introduction schematic direction of the solution B to be mixed; 16. and feeding the solution B or C to be mixed in the schematic direction.

Detailed Description

The present invention will be described in further detail with reference to the drawings and embodiments. It is to be understood that the specific embodiments described herein are merely illustrative of the substances, and not restrictive of the invention. It should be further noted that, for convenience of description, only the portions related to the present invention are shown in the drawings.

In addition, the embodiments of the present invention and the features of the embodiments may be combined with each other without collision. The technical scheme of the present invention will be described in detail below with reference to the accompanying drawings in combination with embodiments.

Unless otherwise indicated, the exemplary implementations/embodiments shown are to be understood as providing exemplary features of various details of some of the ways in which the technical concepts of the present invention may be practiced. Thus, unless otherwise indicated, the features of the various implementations/embodiments may be additionally combined, separated, interchanged, and/or rearranged without departing from the technical concepts of the present invention.

The use of cross-hatching and/or shading in the drawings is typically used to clarify the boundaries between adjacent components. As such, the presence or absence of cross-hatching or shading does not convey or represent any preference or requirement for a particular material, material property, dimension, proportion, commonality between illustrated components, and/or any other characteristic, attribute, property, etc. of a component, unless indicated. In addition, in the drawings, the size and relative sizes of elements may be exaggerated for clarity and/or descriptive purposes. While the exemplary embodiments may be variously implemented, the specific process sequences may be performed in a different order than that described. For example, two consecutively described processes may be performed substantially simultaneously or in reverse order from that described. Moreover, like reference numerals designate like parts.

When an element is referred to as being "on" or "over", "connected to" or "coupled to" another element, it can be directly on, connected or coupled to the other element or intervening elements may be present. However, when an element is referred to as being "directly on," "directly connected to," or "directly coupled to" another element, there are no intervening elements present. For this reason, the term "connected" may refer to physical connections, electrical connections, and the like, with or without intermediate components.

For descriptive purposes, the invention may use spatially relative terms such as "under … …," under … …, "" under … …, "" lower, "" above … …, "" upper, "" above … …, "" higher "and" side (e.g., as in "sidewall") to describe one component's relationship to another (other) component as illustrated in the figures. In addition to the orientations depicted in the drawings, the spatially relative terms are intended to encompass different orientations of the device in use, operation, and/or manufacture. For example, if the device in the figures is turned over, elements described as "under" or "beneath" other elements or features would then be oriented "over" the other elements or features. Thus, the exemplary term "below" … … can encompass both an orientation of "above" and "below". Furthermore, the device may be otherwise positioned (e.g., rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly.

The terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, when the terms "comprises" and/or "comprising," and variations thereof, are used in the present specification, the presence of stated features, integers, steps, operations, elements, components, and/or groups thereof is described, but the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof is not precluded. It is also noted that, as used herein, the terms "substantially," "about," and other similar terms are used as approximation terms and not as degree terms, and as such, are used to explain the inherent deviations of measured, calculated, and/or provided values that would be recognized by one of ordinary skill in the art.

The detection method disclosed by the invention adopts a general method disclosed by the prior art to operate if no special description exists.

The specific embodiments of the invention are as follows:

fig. 1 to 3 are schematic structural views of a capillary array integrated plate according to the present invention.

As shown in fig. 1 to 3, the capillary array collecting plate of the present invention comprises a cylindrical collecting plate 1 and capillaries 2 vertically connected to one side of the collecting plate 1; the lumen 3 of the capillary tube 2 passes through the plate 1 to the other side of the plate (as shown in the partial cross-sectional view of fig. 4);

example 1,

As shown in fig. 5, the capillary array integrated plate is cylindrical with the diameter of 8mm and the thickness of 1.2mm, and 7 capillaries are circularly arranged; the length of the capillary tube is 15mm, the outer diameter is 0.3mm, and the wall thickness of the capillary tube is 0.1mm; the inner cavity 3 of the capillary tube passes through the collecting plate 1 to the other side of the collecting plate;

as shown in fig. 11, the capillary of the capillary array integrated board shown in fig. 5 is put downwards into the upper sample injection groove 6 of the multi-channel base matched with the capillary array integrated board, and the capillary 2 enters the mixing channel 5 and is positioned at the upper part of the mixing channel 5;

in the multi-channel base of fig. 11-13, the overall length of the multi-channel base 4 is 53mm, the upper side surface comprises an upper sample injection groove 6 with the diameter of 8.5mm, the left side surface and the right side surface of the multi-channel base respectively comprise a left sample injection groove 7 and a right sample injection groove 8 with the diameter of 6.3mm, and the lower side surface of the multi-channel base 4 comprises a mixed sample outlet groove 9 with the diameter of 8.5 mm; the upper sample feeding groove 6 and the mixed sample discharging groove 9 are communicated through a mixing channel 5 with the diameter of 2.1mm and the length of 43 mm; the left sample injection groove 7 and the right sample injection groove 8 are communicated with the mixing channel 5 through a left sample injection channel 10 and a right sample injection channel 11 with diameters of 2mm respectively; the distance between the centers of the left sample injection channel 10 and the right sample injection channel 11 and the bottom end of the upper sample injection groove 6 is 6mm;

in the embodiment, the upper sample injection groove 6, the left sample injection groove 7, the right sample injection groove 8 and the mixed sample outlet groove 9 are round;

in practical use, as shown in fig. 14, the solution to be mixed a is introduced into the sample injection groove on the capillary array integrated plate from the sample injection groove, the sample injection direction 15 of the solution to be mixed B and the sample injection direction 16 of the solution to be mixed B or C are introduced into the sample injection pipe from the left and right of the multichannel base, the mixed solution is contacted and mixed in the mixing channel 5 of the multichannel base to form lipid nano particles, and the mixed solution containing the lipid nano particles flows out from the liquid outlet of the multichannel base, as shown in fig. 14, the sample injection direction 14 is mixed;

the upper sample injection groove is filled with a solution A to be mixed, the left sample injection groove and the right sample injection groove are filled with a solution B to be mixed, the solution B to be mixed enters a mixing channel through a left sample injection channel and a right sample injection channel respectively, the solution A to be mixed enters the mixing channel from the upper end of a capillary array integrated plate through a capillary cavity and contacts with the solution B to be mixed in the mixing channel, the solution A to be mixed moves downwards together with the solution B to be mixed while transversely diffusing, and flows through the whole mixing channel, and in the process of flowing through the mixing channel, lipid components in the solution A to be mixed wrap mRNA in the solution B to be mixed to form lipid nano particles;

in other embodiments of the present invention, as shown in fig. 6 to 10, 13, 19, 31 capillaries are used; capillary length 15mm, 21mm; preparing lipid nano particles by using a capillary array integrated plate with the inner diameter of a capillary of 0.1mm and the inner diameter of a capillary of 0.3mm;

the specific parameters are as follows:

the capillary array integrated plate of FIG. 6 has 13 capillaries 2 arranged in a circular shape; the length of the capillary tube 2 is 15mm, the outer diameter is 0.3mm, and the wall thickness of the capillary tube is 0.1mm;

the capillary array integrated plate of FIG. 7 has 19 capillaries 2 arranged in a circular shape; the length of the capillary tube 2 is 15mm, the outer diameter is 0.3mm, and the wall thickness of the capillary tube is 0.1mm;

the capillary array integrated plate of FIG. 8 has 31 capillaries 2 arranged in a circular shape; the length of the capillary tube 2 is 15mm, the outer diameter is 0.3mm, and the wall thickness of the capillary tube is 0.1mm;

the capillary array integrated plate of fig. 9 has 13 capillaries 2 arranged in a circular shape; the length of the capillary tube 2 is 15mm, the outer diameter is 0.5mm, and the wall thickness of the capillary tube is 0.1mm;

the capillary array integrated plate of fig. 10 has 13 capillaries 2 arranged in a circular shape; the length of the capillary tube 2 is 21mm, the outer diameter is 0.3mm, and the wall thickness of the capillary tube is 0.1mm;

EXAMPLE 2,

The capillary array integrated plates of fig. 5 (serial number 1), fig. 6 (serial number 2), fig. 7 (serial number 3), fig. 8 (serial number 4), fig. 9 (serial number 5) and fig. 10 (serial number 6) of example 1 are matched with a matched multichannel base, lipid nanoparticles are prepared by adopting the similar operation of the example, the particle size, PDI and encapsulation efficiency of the prepared lipid nanoparticles are detected, and compared with lipid nanoparticles prepared by a microfluidic chip sold in the prior art;

in this embodiment, the solution to be mixed a is a lipid solution, and the solution to be mixed B is an aqueous solution, and the specific operations are as follows:

the lipid solution is ethanol solution comprising SM102 and CHOL, DSPC, DMG-PEG2000, wherein the concentration of SM102 is 18mg/mL, the concentration of CHOL is 7.55mg/mL, the concentration of DSPC is 4.01mg/mL, and the concentration of DMG-PEG2000 is 1.91mg/mL; the aqueous solution was 500mmol/L PBS buffer containing mRNA at a concentration of 0.5 mg/mL;

the lipid solution enters a mixing channel from an upper sample injection groove through a capillary cavity of a capillary array integrated plate, the aqueous solution enters the mixing channel from a left sample injection groove and a right sample injection groove through the left sample injection channel and the right sample injection channel, the lipid solution starts to contact with the aqueous solution at a capillary outlet, and moves downwards together with the aqueous solution while transversely diffusing, and flows through the whole mixing channel, the lipid component in the lipid solution wraps mRNA in the aqueous solution to form lipid nano particles, and in the whole process, the total flow rate of the lipid solution and the aqueous solution is 50mL/min, 80mL/min, 100mL/min, 120mL/min, 240mL/min, 300mL/min, 360mL/min and 600mL/min (the flow rate ratio of the aqueous solution to the lipid phase solution is 3:1), and the lipid nano particle liquid flowing out of the mixing sample injection groove is collected;

in comparison with a commercially available micro-fluidic mainer chip (serial number 7), the hybrid core structure of the commercially available mainer chip is shown in fig. 15, and the structure is a hybrid flow channel structure of a multi-angle inflection path typical in the prior art; the lipid phase solution and the aqueous phase solution respectively enter from left and right sample inlets, are mixed and contacted in a mixed flow channel of a multi-angle bending path, and the lipid nanoparticle liquid is collected from an outlet of the mixed flow channel, and other conditions are the same as the above;

the lipid nanoparticles obtained were collected, and the particle size, PDI, and encapsulation efficiency were measured, and the results are shown in tables 1 to 3 below;

TABLE 1 particle size (nm) detection data

Flow rate (mL/min)	50	80	100	120	240	300	360	600
									Number 1	65.48	60.51	60.23	58.8	58.49	56.13	55.71	57.56
Number 2	76.12	76.33	73.76	72.68	72.55	68.01	67.92	67.67
									Number 3	68.72	69.01	69.95	68.86	68.70	67.32	67.33	66.98
Number 4	71.77	69.56	69.35	69.76	68.33	67.92	63.24	65.33
									Number 5	85.23	85.89	85.18	83.97	81.56	81.55	80.36	80.63
Number 6	87.57	87.11	87.03	87.15	85.34	85.13	84.33	85.34
									Number 7	73.22	72.89	70.88	88.34	-	-	-	-

Table 1 shows the particle size measurement data of lipid nanoparticles obtained by mixing a lipid solution and an aqueous solution using the capillary array collecting plate of the present invention, and as can be seen from the data of Table 1, the particle size fluctuation of the lipid nanoparticles obtained by mixing using the capillary array collecting plate of the present invention is small at a flow rate of 50 to 600 mL/min; the number of the lipid nano particles is between 55 and 70nm when the number of the capillaries is between 7 and 13 and the number of the capillaries is between 1 and 4; serial No. 5, serial No. 6, the particle size of the lipid nanoparticle obtained is between 80 and 90nm when the number of capillaries is 19 to 31;

serial No. 7, mixing with commercially available maianana chip to prepare lipid nano particles, wherein the particle size of the prepared lipid nano particles is between 70 and 75nm at the flow rate of 50 to 100 mL/min; at a flow rate of 120mL/min, the particle size of the prepared lipid nanoparticle is increased to 88.34nm; at flow rates greater than 120mL/min, the mixed preparation of lipid nanoparticles failed due to the damage of the chip structure caused by the high pressure of the liquid.

From the data, compared with the prior commercially available Michaner chip, the capillary array integrated plate can be used for preparing lipid nanoparticles by mixing a lipid solution and a water phase solution at the flow rate of more than 120mL/min, and the prepared lipid nanoparticles have small particle size fluctuation and are beneficial to realizing the application of industrial expansion production;

TABLE 2PDI detection data

Flow rate (mL/min)	50	80	100	120	240	300	360	600
									Number 1	0.149	0.137	0.136	0.116	0.119	0.123	0.119	0.120
Number 2	0.129	0.134	0.129	0.119	0.129	0.124	0.118	0.118
									Number 3	0.137	0.141	0.131	0.128	0.104	0.120	0.106	0.110
Number 4	0.152	0.157	0.151	0.158	0.142	0.153	0.137	0.138
									Number 5	0.157	0.158	0.164	0.149	0.150	0.162	0.128	0.128
Number 6	0.158	0.153	0.159	0.145	0.149	0.159	0.135	0.136
									Number 7	0.158	0.153	0.160	0.189	-	-	-	-

Table 2 shows PDI measurement data of lipid nanoparticles obtained by mixing a lipid solution and an aqueous phase solution by using the capillary array collecting plate of the invention, and as can be seen from the data in Table 2, PDI value fluctuation of the lipid nanoparticles obtained by mixing by using the capillary array collecting plate of the invention is within a reasonable range at a flow rate of 50-600 mL/min; the PDI value of the obtained lipid nano particles is between 0.1 and 0.15 when the number of the capillaries is between 7 and 13 from 1 to 3; the PDI value of the obtained lipid nano particles is between 0.12 and 0.17 when the number of the capillaries is between 5 and 6 and 19 to 31;

the number 4 is 13 capillaries, and when the inner diameter of the capillaries is 0.3mm, the PDI value of the obtained lipid nanoparticle is obviously increased compared with the number 3 (13 capillaries and 0.1mm in the inner diameter of the capillaries);

serial No. 7, mixing with commercially available maianana chip to prepare lipid nano particles, wherein the PDI value of the prepared lipid nano particles is between 0.15 and 0.16 at the flow rate of 50-100 mL/min; the PDI value of the prepared lipid nanoparticle is increased to 0.189 at the flow rate of 120 mL/min; at flow rates greater than 120mL/min, the mixed preparation of lipid nanoparticles failed due to the damage of the chip structure caused by the high pressure of the liquid.

From the data, compared with the prior commercially available Michaner chip, the capillary array integrated plate can be used for preparing lipid nanoparticles by mixing a lipid solution and an aqueous phase solution at a flow rate of more than 120mL/min, and the prepared lipid nanoparticles have small PDI value fluctuation and better polymer dispersibility; particularly, the capillary array integrated plate with the inner diameter of the capillary tube of 0.1mm can obtain the PDI value of the lipid nano particles of 0.1-0.13 at the flow rate of more than 240mL/min, and the polymer dispersion is remarkably excellent; the method is favorable for realizing the application of industrialized enlarged production;

table 3 encapsulation (%) test data

Flow rate (mL/min)	50	80	100	120	240	300	360	600
									Number 1	90.12	90.18	93.34	93.97	95.84	95.49	95.94	95.35
Number 2	90.75	90.17	90.09	90.67	95.72	96.03	96.25	95.86
									Number 3	90.53	90.67	91.05	92.69	93.89	95.22	96.10	96.00
Number 4	91.34	92.43	92.78	94.09	93.98	95.26	96.31	96.89
									Number 5	89.98	89.89	90.56	90.32	91.12	91.09	91.23	92.00
Number 6	89.86	89.78	89.88	90.43	91.34	91.78	91.34	91.45
									Number 7	91.12	91.78	87.45	81.65	-	-	-	-

Table 3 shows the measurement data of the encapsulation efficiency of the lipid nanoparticles obtained by mixing the lipid solution and the aqueous phase solution using the capillary array collecting plate of the present invention, and as can be seen from the data of Table 3, the encapsulation efficiency of the lipid nanoparticles obtained by mixing using the capillary array collecting plate of the present invention is more than 89% at a flow rate of 50-600 mL/min; especially, when the number of the capillaries is from 1 to 4 and 7 to 13, the encapsulation rate of the lipid nano particles obtained at a high flow rate of 300 to 600mL/min is more than 95 percent; the encapsulation rate of the obtained lipid nano particles is 89% -92% when the number of the capillaries is 19-31 from 5 to 6;

serial No. 7, mixing with commercially available maianana chip to prepare lipid nano particles, wherein the encapsulation rate of the prepared lipid nano particles is between 81 and 92 percent at the flow rate of 50 to 100 mL/min; the PDI encapsulation efficiency of the prepared lipid nanoparticle is reduced to 81.65% at the flow rate of 120 mL/min; at flow rates greater than 120mL/min, the mixed preparation of lipid nanoparticles failed due to the damage of the chip structure caused by the high pressure of the liquid.

From the data, compared with the prior commercially available Michaner chip, the capillary array integrated plate can be used for preparing lipid nanoparticles by mixing a lipid solution and an aqueous phase solution at a flow rate of more than 120mL/min, and the prepared lipid nanoparticles have good encapsulation efficiency and are beneficial to the encapsulation and delivery of mRNA active components; particularly, when the flow rate is more than 240mL/min, the encapsulation rate of the obtained lipid nanoparticle is more than 95%, and the remarkably excellent encapsulation effect is shown; the application of the mRNA drug industrialized enlarged production is facilitated;

in other embodiments of the present invention, similar benefits as described above are still obtained when the total flow rate of the liquid is greater than 600mL/min when microfluidic mixing is performed.

In other specific embodiments of the invention, the device is used for the mixed preparation of the lipid polymer coated nucleic acid drug, the mixed preparation of LNP coated siRNA or ASO or miRNA or saRNA or Aptamer, and has similar beneficial effects as described above under the condition that the total flow rate of liquid is greater than 100mL/min when microfluidic mixing is carried out.

In summary, compared with the microfluidic mixing chip or device disclosed by the prior art, the capillary array collecting plate disclosed by the invention can be used for performing microfluidic mixing preparation of lipid nanoparticles together with the matched multichannel base under the condition of total flow rate of more than 120mL/min, and the prepared lipid nanoparticles are stable and reliable in quality; can realize the application of industrial amplified production in workshops.

Claims

1. A capillary array integrated plate for microfluidic mixing equipment, characterized in that: comprises a collecting plate (1) and a capillary tube (2) connected with the collecting plate; one end of the capillary tube (2) is connected to the collecting plate (1), and the inner cavity (3) of the capillary tube (2) penetrates through the collecting plate; the number of the capillaries (2) is 2-100, and the inner diameter is 0.01-5 mm.

2. The capillary array collection sheet of claim 1, wherein: 7-50 capillaries (2); the length of the capillary tube (2) is 10-100 mm; preferably 15 to 21mm.

3. The capillary array collection sheet of claim 1, wherein: the collecting plate (1) is one of a cylinder, an elliptic cylinder, a square cylinder, a trapezoid cylinder, a hexagonal cylinder, a pentagonal cylinder, a triangular cylinder and a star-shaped cylinder; the collecting plate (1) is preferably cylindrical and has a diameter of 1-100 mm.

4. The capillary array collection sheet of claim 1, wherein: the array of capillaries (2) is arranged in one or more of circular arrangement, square arrangement, elliptic arrangement, triangular arrangement, hexagonal arrangement, pentagonal arrangement, trapezoidal arrangement, star arrangement or random arrangement.

5. A multi-channel mount for use with the capillary array manifold of claim 1, wherein: comprises a mixing channel (5) and a sample injection channel; the sample injection channel is communicated with the mixing channel (5); the sample injection channel comprises a left sample injection channel (10) and a right sample injection channel (11).

6. The multi-channel base of claim 5, wherein: the matched capillary tubes of the capillary array integrated plate extend into the mixing channel.

7. The multi-channel base of claim 5, wherein: the upper side surface of the multichannel base (4) comprises an upper sample injection groove (6), the left side surface and the right side surface of the multichannel base respectively comprise a left sample injection groove (7) and a right sample injection groove (8), and the lower side surface of the multichannel base comprises a mixed sample outlet groove (9); the upper sample feeding groove (6) is communicated with the mixing sample discharging groove (9) through the mixing channel (5); the left sample injection groove (7) and the right sample injection groove (8) are communicated with the mixing channel (5) through a left sample injection channel (10) and a right sample injection channel (11) respectively.

8. The multi-channel base of claim 5, wherein: the distance between the left sample injection channel (10), the right sample injection channel (11) and the upper sample injection groove (6) is smaller than the length of the capillary tube (2);

the size of the upper sample feeding groove (6) is not smaller than the size of the collecting plate (1) of the capillary array collecting plate.

9. The multi-channel base of claim 6, wherein: the length of the mixing channel (5) is 10-1000 mm;

the diameter of the mixing channel (5) is 1-100 mm.