CN108949565A - Device and method for red blood cell load freeze drying protectant - Google Patents
Device and method for red blood cell load freeze drying protectant Download PDFInfo
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- CN108949565A CN108949565A CN201811146525.0A CN201811146525A CN108949565A CN 108949565 A CN108949565 A CN 108949565A CN 201811146525 A CN201811146525 A CN 201811146525A CN 108949565 A CN108949565 A CN 108949565A
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M23/00—Constructional details, e.g. recesses, hinges
- C12M23/02—Form or structure of the vessel
- C12M23/16—Microfluidic devices; Capillary tubes
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
- C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
Abstract
The present invention provides a kind of device and method for red blood cell load freeze drying protectant, which includes: the first chip, and lower surface has first passage, and first passage includes multiple entrances and the first mixer；Second chip, positioned at the lower section of the first chip, upper surface has second channel, which includes entrance and the second mixer, and lower surface has third channel, and third channel includes mass exchange area；Third chip, positioned at the lower section of the second chip, upper surface has fourth lane, and fourth lane includes mass exchange area；At least four first perforated membranes；And at least a piece of second perforated membrane；The first passage of first chip is connected to the second channel of the second chip；The second channel of second chip is connected to third channel.Device and method of the present invention for red blood cell load freeze drying protectant, can effectively, automatically load freeze drying protectant in red blood cell, improve Erythrocytes in Freeze Drying survival rate and the rate of recovery, have preferable convenience.
Description
Technical field
The present invention relates to the field of medical instrument technology more particularly to a kind of devices for red blood cell load freeze drying protectant
And method.
Background technique
Freeze-drying is a kind of common method for being used for long-term preservation red blood cell (RBCs), especially to the cell for saving preciousness
Be of great significance, it there are many be better than conventional method the advantages of, such as can room temperature storage, performance stablize, be readily transported.For
Reduce freezing dry process in cell low temperature injury, often need be added in the cell suspending liquid of preservation it is certain density certain
Freeze drying protectant.The integrality for maintaining erythrocyte membrane is to realize the important prerequisite of RBCs of freeze-drying preservation.Trehalose is a kind of day
So existing disaccharides, some researches show that there are trehaloses can enhance red blood cell to cold and dry tolerance for cell membrane two sides.
But since trehalose is a kind of impermeability protective agent, it is therefore desirable to propose that effective method makes red blood cell trehalose.
The method of current Trehalose Loading Red Blood Cells mainly has liposome method, electroporation, synthetic method and hatching method.
In liposome method, enter in red blood cell after several hours of the liposome containing trehalose after hatching.In electroporation,
Under certain electric field strength, cell membrane pore-forming, trehalose in the hole on cell membrane by being supported, this process is to cell membrane
Cause irreversible damage.Synthetic method uses PP-50, and a kind of biopolymer of synthesis is double to improve red blood cell phosphatide
Layer permeability of the membrane, to reach trehalose.But process complexity effort and PP-50 to the physiological effect of red blood cell need into
One step confirms.In hatching method, red blood cell is incubated for for a long time in hypertonicity aqueous trehalose.In short, the above method usually needs
Want many more manipulations and long time treatment.
Osmotic pressure hole forming method is a kind of method of simple, effective red blood cell carrying medicament, in the past few years
Through being applied in red blood cell trehalose.However, the result of different experiments is (for example, load effect in the research to this method
Rate and cell survival rate) it is different.Its reason is mainly that experiment flow is diversified.Therefore, freeze-drying and rehydration are ground
The result studied carefully is also different.In order to preferably study the correlated condition of red blood cell freeze-drying, it is necessary to develop one kind and be based on
Principle load freeze drying protectant (trehalose) of hypotonic pore-forming is in the device of red blood cell.
Summary of the invention
(1) technical problems to be solved
In view of the above problems, the main purpose of the present invention is to provide a kind of dresses for red blood cell load freeze drying protectant
It sets and method, at least one of to solve the above problems.
(2) technical solution
In order to achieve the above object, it as one aspect of the present invention, provides a kind of for red blood cell load freeze-drying guarantor
Protect the device of agent, comprising:
First chip, lower surface have first passage, which includes multiple entrances and the first mixer；
Second chip, positioned at the lower section of first chip, upper surface has a second channel, the second channel include into
Mouth and the second mixer, lower surface have third channel, which includes mass exchange area and outlet；
Third chip, positioned at the lower section of second chip, upper surface has a fourth lane, the fourth lane include into
Mouth, mass exchange area and outlet；
At least four first perforated membranes: the following table face paste of the first surface of first first perforated membrane and first chip
It closes；The first surface of second first perforated membrane is opposite with the second surface of first first perforated membrane, and second first
The second surface of perforated membrane is bonded with the upper surface of second chip；The first surface of the first perforated membrane of third piece and described the
The lower surface of two chips is bonded；The second surface of the first surface of 4th first perforated membrane and first perforated membrane of third piece
Relatively, the second surface of the 4th first perforated membrane is bonded with the upper surface of the third chip；
At least a piece of second perforated membrane, is arranged in the mass exchange area of second chip and the mass exchange of third chip
Between area, first surface covers the mass exchange area of second chip, and second surface covers the substance of the third chip
Exchange area；
The first passage of first chip is connected to the second channel of second chip；The second of second chip
Channel is connected to third channel.
In some embodiments, thickness of the depth of the first passage less than the first chip；The depth of the second channel
Spend the thickness less than the second chip；Thickness of the depth of the third channel less than the second chip；The depth of the fourth lane
Less than the thickness of third chip.
In some embodiments, the first passage includes first entrance and second entrance, and first entrance is low for flowing into
Osmometer solution, second entrance are used to mix through the low of first entrance inflow for flowing into red blood cell suspension, first mixer
Osmometer solution and the red blood cell suspension flowed into through second entrance；
The second channel includes third entrance, and for flowing into hypertonic solution, second mixer is for mixing through the
The hypertonic solution that three entrances flow into and the mixed liquor mixed through the first mixer, obtain the red blood cell suspension of load freeze drying protectant
Liquid；
The fourth lane includes the 4th entrance and first outlet, and the 4th entrance is for flowing into isotonic solution；It is described isotonic
Solution is flow to the mass exchange area of third chip, the red blood cell suspension warp of the load freeze drying protectant by fourth lane
It flow to the mass exchange area of the second chip by second channel, third channel, carries out mass exchange, institute with the isotonic solution
First outlet is stated for the isotonic solution after flowing out exchange；
The third channel includes second outlet, for flowing out the red blood cell suspension of the load freeze drying protectant after exchanging
Liquid；
The first passage of first chip is connected to the second channel of second chip, for making the first passage
In mixed solution enter the second channel；The second channel of second chip is connected to third channel, described for making
The mixed solution of second channel enters the third channel.
In some embodiments, being arranged on the first perforated membrane of two panels between second chip and third chip has
Multiple openings, second perforated membrane are arranged between first perforated membrane of two panels, cover the multiple opening.
In some embodiments, first chip, the second chip, third chip material be organic glass or poly- diformazan
Radical siloxane, first perforated membrane are silica gel perforated membrane, and the second perforated membrane is poly (ether sulfone) film or polyvinylidene fluoride microporous filtering film.
In some embodiments, the area of first chip, the second chip and third chip between 70 square centimeters~
Between 150 square centimeters；The thickness of first chip, the second chip and third chip is between 5 millimeters~10 millimeters；
First perforated membrane with a thickness of 0.1 millimeter~0.5 millimeter, the aperture of first perforated membrane is 20 microns~
50 microns；The aperture of second perforated membrane is 0.1 micron~1.2 microns.
In some embodiments, first chip, the second chip and third chip are distributed in staged；Described first is logical
Road and second channel use T-type tandem type distributed architecture, respectively include interconnection and the vertical passage perpendicular to interconnection,
The interconnection is connected to vertical passage；First mixer, the second mixer are S-shaped mixer.
In some embodiments, the first passage, second channel and third channel are rectangular recess structure, rectangular recess
Width be greater than groove depth.
In some embodiments, have the rectangular recess there are four miniature rectangular column, square centered on the mass exchange area
The width of connected in star is greater than the depth of groove, and the miniature rectangular column is used to support second perforated membrane.
It is a kind of another aspect of the present disclosure provides to carry out red blood cell load frozen-dried protective using the device
The method of agent, comprising:
Red blood cell suspension is poured into from the first entrance of the first passage of the first chip of described device, by hypotonic solution
It is poured into from the second entrance of the first passage of first chip, red blood cell suspension and hypotonic solution are in first chip
It is uniformly mixed at first mixer, mixed liquor flows into the second mixer of the second chip through first passage；
Hypertonic solution is poured into from the third inlet of the second channel of second chip, hypertonic solution and the mixing
It is uniformly mixed at liquid stream to the second mixer of the second chip, and the second channel through the second chip, third channel flow to second
Chip mass exchange area；
Isotonic solution is poured into from the 4th inlet of the fourth lane of the third chip, isotonic solution is along four-way
Road flowing, flow to the mass exchange area of the third chip, carries out substance friendship with the mixed liquor in the mass exchange area of the second chip
It changes.
(3) beneficial effect
It can be seen from the above technical proposal that a kind of device and method for red blood cell load freeze drying protectant of the present invention
At least have the advantages that one of them:
(1) present invention for red blood cell load freeze drying protectant device and method, use is hypotonic, hypertonic solution can be more
Effectively, freeze drying protectant is automatically loaded in red blood cell, improves Erythrocytes in Freeze Drying survival rate and the rate of recovery.
(2) device and method of red blood cell trehalose of the present invention have automatic load freeze drying protectant, blood plasma separation,
The multiple functions such as cell culture and drug screening have preferable convenience.
Detailed description of the invention
The embodiment of the present invention or technical solution in the prior art are explained in detail in order to become apparent from, it below will be to embodiment
Or attached drawing needed to be used in the description of the prior art is briefly described, it should be apparent that, the accompanying drawings in the following description is only
It is the embodiment of the present invention, it for those of ordinary skill in the art, without creative efforts, can be with
Other attached drawings are obtained according to the attached drawing of offer.
Fig. 1 is that the red blood cell provided in the embodiment of the present invention loads freeze drying protectant apparatus structure schematic diagram；
Fig. 2 is that the red blood cell provided in the embodiment of the present invention loads the structure of the first chip lower layer in freeze drying protectant device
Schematic diagram；
Fig. 3 is that the red blood cell provided in the embodiment of the present invention loads the structure on the second chip upper layer in freeze drying protectant device
Schematic diagram；
Fig. 4 is that the red blood cell provided in the embodiment of the present invention loads the structure of the second chip lower layer in freeze drying protectant device
Schematic diagram；
Fig. 5 is that the red blood cell provided in the embodiment of the present invention loads the structure on third chip upper layer in freeze drying protectant device
Schematic diagram.
Specific embodiment
To make the objectives, technical solutions, and advantages of the present invention clearer, below in conjunction with specific embodiment, and reference
Attached drawing, the present invention is described in further detail.
Following will be combined with the drawings in the embodiments of the present invention, and technical solution in the embodiment of the present invention carries out clear, complete
Site preparation description, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.It is based on
Embodiment in the present invention, it is obtained by those of ordinary skill in the art without making creative efforts every other
Embodiment shall fall within the protection scope of the present invention.
With the development of microflow control technique, it is widely used bioprocess and biomedicine, such as biological detection, medicine
Object screening, biological sample processing and Bioexperiment etc., microflow control technique has been that red blood cell trehalose opens a road Xiang Xin
Diameter, to realize the process of the trehalose on chip.
The present invention proposes a kind of device for red blood cell load freeze drying protectant, the specially principle based on hypotonic pore-forming
Freeze drying protectant is loaded in the device of red blood cell.As shown in Figs. 1-5, the present invention is based on the principles of hypotonic pore-forming to load frozen-dried protective
Agent (being trehalose specific to the present embodiment) is in the device (being micro-fluidic chip specific to the present embodiment) of red blood cell, comprising:
The first chip 10 with first passage, for the depth of the first passage less than the thickness of the first chip, first is logical
Road is located at the lower surface of the first chip, and first passage includes multiple entrances 1,2 and the first mixer 8；
The second chip 20 with second channel, for the depth of the second channel less than the thickness of the second chip, second is logical
Road is located at the upper surface of the second chip, and second channel includes entrance 3 and the second mixer 9；
The second chip 20 with third channel, the depth of the third channel less than the second chip thickness, described
Triple channel is located at the lower surface of the second chip, and third channel includes mass exchange area 11 and outlet 7；
Third chip 30 with fourth lane, the depth of the fourth lane are less than the thickness of third chip, and described the
Four-way is located at the upper surface of third chip, and fourth lane includes entrance 5, mass exchange area 10, outlet 6；
First chip, the second chip and third chip are arranged successively from top to bottom；
It is arranged between first chip and the second chip and first porous between the second chip and third chip
Film 40, totally four, first one side of first perforated membrane is bonded with the lower surface of first chip, another side and
The one side covering of two perforated membranes, second perforated membrane another side is bonded with the upper surface of second chip, more than described first
The one side of the third piece of pore membrane is bonded with the lower surface of second chip, and the one side of another side and the 4th perforated membrane covers,
4th perforated membrane another side is bonded with the upper surface of the third chip；
The second perforated membrane between the mass exchange area of second chip and the mass exchange area of third chip is set
50, the one side of second perforated membrane covers the mass exchange area of second chip, and another side covers the third chip
Mass exchange area；
The circulation point of first chip and circulation point (circulation point for example, through-hole, the tool of second chip are set
Body is the through-hole that solution can be made to flow to the second chip by the first chip) and second chip upper layer circulation point and it is described
Second chip lower layer circulation point can be completely coincident, and pass through the mixed solution of the first passage described in circulation point entrance
Second channel allows the mixed solution of the second channel to enter the third channel by circulation point；
The entrance and exit of each layer chip is independent between each other.
As shown in Figure 1, having on the first perforated membrane of two panels being arranged between second chip and third chip multiple
Opening, second perforated membrane are arranged between first perforated membrane of two panels, cover the multiple opening.
Using apparatus of the present invention, cell suspending liquid (specially red blood cell suspension) enters the from an entrance of first passage
The first passage of one chip, hypotonic solution (freeze drying protectant be trehalose when, hypotonic solution, that is, hypotonic aqueous trehalose) from
Another entrance of first passage enters the first passage of the first chip, after mixing in the mixer of the first chip, through a hole
(not shown) flows to the second channel of the second chip from the first chip, and hypertonic solution is (hypertonic when freeze drying protectant is trehalose
Solution, that is, hypertonic aqueous trehalose) from the entrance of the second chip into the second channel of the second chip, in the mixing of the second chip
After device mixing, the third channel of the second chip is entered through a hole, the mass exchange area of the second chip is flow to through third channel, etc.
Osmometer solution flows into the fourth lane of third chip from the entrance of third chip, and the mass exchange of third chip is flow to through fourth lane
The mixed liquor in area, the isotonic solution in third chip mass exchange area and the second chip mass exchange area carries out mass exchange, exchange
Cell suspending liquid is flowed out from the outlet of the second chip lower surface third channel later, and the isotonic solution after exchanging is through third chip
Fourth lane outlet outflow.
In an embodiment of the present invention, the shape of first chip can be rectangular or round, but the present invention is to described
The shape of first chip does not have special limitation, meets practical operation condition.The area of first chip can be 70
Square centimeter~150 square centimeters, thickness can be 5 millimeters~10 millimeters.The present invention uses the lesser first chip energy of area
The whole size for enough reducing red blood cell trehalose device, makes the micro-fluidic core of red blood cell trehalose provided by the invention
Piece has preferable portability.In an embodiment of the present invention, first chip is rectangular, and rectangular length can be 10 centimetres
~15 centimetres, wide can be 7 centimetres~10 centimetres.First chip, the second chip and third chip are distributed in staged.
In an embodiment of the present invention, the material of first chip can be organic glass (PMMA) or poly dimethyl silicon
Oxygen alkane (PDMS)；The present invention does not have special limitation to the type of the organic glass and PDMS and source, using this field skill
Organic glass known to art personnel and PDMS can be bought by market and be obtained；As in embodiment, Suzhou river in Shangdong Province white can be used
The PDMS polymer of organic glass or the healthy and free from worry offer of Michigan, United States Midland that chip Science and Technology Ltd. provides.
In an embodiment of the present invention, the first passage use T-type tandem type distributed architecture, including interconnection and hang down
Directly in the vertical passage of interconnection, the interconnection is connected to vertical passage.In an embodiment of the present invention, described
First passage is set as a major trunk roads.In an embodiment of the present invention, the first passage is rectangular recess, the groove
Width is greater than the depth of groove, thereby enhances the convection effects of transport materials flowing, improves the flowing velocity of transport materials；
And the larger resistance that can also reduce transport materials flowing of width of the groove, to reduce the driving of transport materials flowing
Power keeps load freeze drying protectant (trehalose) provided by the invention small in the device kinetic equation loss of red blood cell.In reality of the invention
It applies in example, the width in the rectangular recess channel can be 1mm, and depth can be 0.5mm；In other examples, described
The width in channel can be 0.8mm~1.2mm, and depth can be 0.3mm~0.5mm.The present invention uses size smaller channels energy
Enough be conducive to be flowed using the pressure difference inside and outside cell membrane as drive force substance from mass transfer is driven, be conducive to bear
Freeze drying protectant (trehalose) is carried in red blood cell.
In an embodiment of the present invention, first mixer uses S type mixer, by hypotonic solution and red blood cell suspension
Liquid mixing can make fluid more quickly, uniformly mix, it is ensured that fluid can be mixed adequately, so that red blood cell
The pore-forming in hypotonic aqueous trehalose, aqueous trehalose is entered in red blood cell by the hole on cell membrane, so that the present invention be made to mention
The load freeze drying protectant of confession can automatically make red blood cell pore-forming in hypotonic solution in the device of red blood cell.
In an embodiment of the present invention, the second channel is the channel of genesis analysis, can reduce channel occupied space, with
First chip is matched.The mixed liquor of hypotonic aqueous trehalose and cell suspending liquid that first chip is formed, in institute
It states and converges at the second chip with hypertonic aqueous trehalose, flow to second mixer, second mixer is the mixing of S type
Device, as shown in Figs. 1-3.
In an embodiment of the present invention, the material type one of the material type of second chip and first chip
It causes, the size of second chip is consistent with the size of first chip, and details are not described herein again.The S type of second chip
Shape, size and the size of mixer are consistent with the S type mixer of first chip, can make fluid more quickly,
Even mixing, it is ensured that the hypotonic aqueous trehalose of formation of first chip and the mixed liquor of cell suspending liquid are in second core
Piece can be mixed adequately with hypertonic aqueous trehalose, so that the hole being loaded on the erythrocyte membrane of trehalose is in hypertonic trehalose
The closing of solution mesoporous, realizes the overall process of red blood cell trehalose.In addition, can change mixing according to different implementation purposes
The type of device.
In an embodiment of the present invention, the fourth lane of the mass exchange area of second chip and third chip is independent,
The mass exchange area of second chip and the mass exchange area of the third chip are completely coincident, and are had centered on shape
The rectangular recess of four miniature rectangular columns, the miniature rectangular column support the mass exchange film being made of the second perforated membrane, institute
The width for stating groove is greater than the depth of groove.Rectangular recess width be 0.5mm, the outlet in the mass exchange area of the third chip with
The fourth lane connection.The mass exchange area can enclose a floor second perforated membrane, and the size of the second perforated membrane is bigger
Size in mass exchange area.
In an embodiment of the present invention, the material type one of the material type of the third chip and first chip
It causes, the size of the third chip is consistent with the size of first chip, and details are not described herein again.
In an embodiment of the present invention, the mass exchange area in the mass exchange area of the third chip and second chip
Size and in the same size, details are not described herein again；The substance of the mass exchange area of the third chip and second chip is handed over
Changing area can be completely coincident, and then ensure that the third chip and second chip can be completely coincident, the third chip
Mass exchange area with the second chip be it is identical, so that the cell suspending liquid of second chip is flowed through the mass exchange
Film can be such that the laminar flow of cell suspending liquid and isotonic solution (such as isotonic physiological saline solution) under mass exchange effect makees
With generating higher mass transfer efficiency, promote the uniform mixing of cell suspending liquid and isotonic physiological saline solution, keep cell outstanding
Free hemoglobin in supernatant liquid is by rapid dilution and removal；Finally make load freeze drying protectant (trehalose) provided by the invention
In the device of red blood cell may be implemented continuity, automatically trehalose in red blood cell.
In an embodiment of the present invention, first perforated membrane can be by the hypotonic solution and red blood cell suspension in first passage
The mixed liquor of liquid is separated with the hypertonic solution in second channel described in the second channel, them is avoided to contact with each other, described
The removing of free hemoglobin is carried out in mass exchange area, first perforated membrane is simultaneously by the third channel and the described 4th
Channel separates, make it is provided by the invention load freeze drying protectant (trehalose) in red blood cell device have reduce cellular damage and
The multiple functions such as free hemoglobin in cell suspending liquid are quickly and efficiently removed, there is better practicability.
In an embodiment of the present invention, first perforated membrane can be silicon rubber perforated membrane；Preferably, more than described first
Pore membrane can be the silicon rubber that is main chain containing polysiloxanes, this to can be resistant to height containing the silicon rubber that polysiloxane is main chain
Temperature, thickness uniformly, any surface finish, it is transparent, with certain intensity and elasticity, not yellowing；With elasticity outstanding, gas permeability,
Characteristic not available for the other elastomers material such as soft and nontoxic, odorlessness, physiological inertia.Therefore, such silicon rubber in addition to
Being widely used in manufacture has outside the rubber product of special high-low temperature resistant requirement, it may also be used for manufacture functional film materials, for for example
In cell culture, human body delicate tissues such as ear-drum liner, field of tissue engineering technology the effects of bracket cladding.The thickness of such silicone rubber membrane
Generally 0.05~0.5 millimeter of degree.In an embodiment of the present invention, the thickness of first perforated membrane can for 0.1 millimeter~
0.5 millimeter；Preferably, first perforated membrane with a thickness of 0.3 millimeter, first perforated membrane of two panels can be effective after being overlapped
Ground avoids the problem that solution exosmoses.In an embodiment of the present invention, the aperture of first perforated membrane is 20 microns~50 microns；
But the present invention does not have special limitation to the type having containing the silicone rubber membrane that polysiloxane is main chain and source, adopts
With silicone rubber membrane well known to those skilled in the art, it can be bought and be obtained by market；It, can be with as in an embodiment of the present invention
The silicone rubber membrane provided using Shanghai conduit limited rubber company.
The present invention does not have special limitation to the shape and size of first perforated membrane, and first perforated membrane can incite somebody to action
The first passage covering, separates the first passage and the second channel, and can cover the third channel,
Third channel and the fourth lane are separated, practical operation condition is met.In an embodiment of the present invention, described first
The shape of perforated membrane can be rectangle, and the length of first perforated membrane can be 10 centimetres~18 centimetres, and wide can be 7 centimetres
~12 centimetres.
In an embodiment of the present invention, the aperture of second perforated membrane can be 0.1 micron~1.2 microns.Described
Two perforated membranes can be poly (ether sulfone) film (PES) or Kynoar pvdf membrane；The wherein miillpore filter of polyether sulfone material, belongs to
Hydrophilic filter membrane has the characteristics that high flow rate, low leachable, good intensity, not adhesion protein and extract, to sample without dirt
Dye.In a preferred embodiment of the invention, second perforated membrane can be hydrophilic poly (ether sulfone) film, this poly (ether sulfone) film tool
There are good hydrophily and flux, good chemical stability and inertia, alkaline PH stablizes, and has high drug compatibility；With very
Good temperature stability energy, full wafer filter membrane can carry out sterilization in the case where guaranteeing integrality at high temperature.And herein
Good anti-contracility energy is kept in the process, avoids reduction and entire mass exchange that the tearing of film, flow velocity occur in filter
The reduction of amount.Its main purposes can be low-protein absorption and high drug compatibility, aim at it is biochemical, examine, pharmacy and
Bactericidal substance switch and design.The aperture of such poly (ether sulfone) film be generally 0.45 micron, 0.6 micron, 0.8 micron, it is 1.0 micro-
Rice and 1.2 microns etc., while can also be according to requiring to customize.In a preferred embodiment of the invention, the second perforated membrane choosing
Biggish aperture is selected, is 1.2 microns；The present invention does not have special limit to the type for having hydrophilic poly (ether sulfone) film and source
System can be bought by market and be obtained using with hydrophilic film；As in an embodiment of the present invention, Shanghai can be used
The film that Haining City neutrality mass exchange equipment Co., Ltd provides.
The present invention does not have special limitation to the shape and size of second perforated membrane, and second perforated membrane can incite somebody to action
The mass exchange area covering, makes to separate with the third channel and the fourth lane, meets practical operation condition.?
In the embodiment of the present invention, the area of second perforated membrane is slightly larger than the area in mass exchange area, can be effectively avoided thin
The extravasation of born of the same parents' suspension achievees the purpose that increase the effect of removal free hemoglobin and reduces the loss cell in removal process.
In an embodiment of the present invention, the entrance of the first passage and the entrance of second channel are independent of each other, institute
Stating entrance 1 in first passage including hypotonic solution and the entrance 2 of cell suspending liquid, (entrance 1, entrance 2 can make hypotonic molten respectively
Liquid, cell suspending liquid are passed through first passage), the second channel includes that (entrance 3 can make hypertonic solution for the entrance 3 of hypertonic solution
It is passed directly into second channel), hypotonic aqueous trehalose and cell suspending liquid are respectively from the hypotonic sea of the first passage of the first chip
Algae sugar juice feeder connection and cell suspending liquid entrance flow into, and the mixer for flowing through the first passage is sufficiently mixed, then is flowed to
The second channel of second chip converges with the hypertonic aqueous trehalose of second channel.
Hypertonic aqueous trehalose is flowed into from the entrance of the second channel, and the mixed liquor of first passage and hypertonic trehalose are molten
Liquid is mixed in the S type mixer of second channel, is realized the overall process of red blood cell trehalose, is then loaded with the red of trehalose
Cell suspending liquid flows into the mass exchange area of the second chip lower surface, and the fourth lane of third chip upper surface, which is passed through, waits vadose solutions
Liquid, isotonic solution (cleaning solution) are independently passed through third chip by isotonic solution entrance, are divided into four by-path cleaning solutions and flow into third
The mass exchange area of chip takes away free hemoglobin and other impurities by second perforated membrane, in the four-way
Recycle mass exchange liquid (aqueous trehalose in the mass exchange area of the third chip after mass exchange) in the outlet in road；Finally exist
The outlet outflow of the third channel is loaded with the device of the cell suspending liquid of trehalose.
Cell suspending liquid and hypotonic trehalose are injected separately into the interconnection of first passage by entrance 1 and entrance 2
Solution, two fluids are sufficiently mixed in the S type mixer of first passage, are flowed through the first passage and are passed through described in through-hole entrance
Second channel converges with the hypertonic aqueous trehalose of second channel and then is sufficiently mixed into S type mixer is crossed.Entrance 3 is not wear
Saturating second chip, but penetrate the hole of the first chip.Hypertonic aqueous trehalose is flowed into from entrance 3, mixed with the first passage
It closes the S type mixer that liquid converges into second chip to be sufficiently mixed, be then flowed under second chip from a hole 4
The mass exchange area of the cell suspending liquid on surface is through-hole at hole 4, the solution in second channel can be made to be passed through third channel.
Entrance 5 is the entrance of fourth lane, isotonic solution can be made to be passed directly into fourth lane), by the upper table of the third chip
The fourth lane in face exchanges cell suspending liquid by mass exchange working substance, returns at the fourth lane outlet 6 of third chip
Receive mass exchange liquid.Outlet 7 is the outlet of the second chip lower surface passage cell suspension, finally going out in the third channel
The solution of red blood cells of trehalose is collected at mouth 7.It please refers to shown in Fig. 1, the entrance 1,2,3,5 can be by each place channel
The upper surface of the first chip is passed to, corresponding solution can be poured into each entrance corresponding position of the first chip upper surface as a result,
It is flowed directly to the corresponding channel of each entrance.
In an embodiment of the present invention, the production method of device of load freeze drying protectant (trehalose) in red blood cell
It can be with are as follows:
By the first chip, the first perforated membrane, the first perforated membrane, the second chip, the first perforated membrane, the second perforated membrane, first
Perforated membrane and third chip are arranged successively from top to bottom, and the lower surface of first chip is provided with first passage, and described second
The upper surface of chip is provided with second channel, makes the upper surface of first first perforated membrane in the underface of first passage, and second
The lower surface of the first perforated membrane of piece is in the surface of second channel, the upper surface of second perforated membrane and first first perforated membrane
Lower surface is completely overlapped；The lower surface of second chip is provided with third channel, and the upper surface of the third chip is provided with
Fourth lane makes the upper surface of the first perforated membrane of third piece in the underface of third channel, the following table of the 4th first perforated membrane
In the surface of fourth lane, the upper surface of the 4th first perforated membrane and the lower surface of the first perforated membrane of third piece are completely heavy in face
Folded, the second perforated membrane is covered on the upper of mass exchange area；It can be by screw by first chip, the second chip and third
Chip is fastenedly connected.
After assembling, the mass exchange area of third channel and the exchange zone position of fourth lane are opposite, in the second chip and
Four openings of the first perforated membrane of two panels between third chip correspond respectively, this four opening respectively with exchange zone position
It corresponds, thus separates third channel and fourth lane using the first perforated membrane of two panels, and expose substance using four openings
Exchange area.Second perforated membrane covers four openings between first perforated membrane of two panels, and corresponding covering material is handed over
Area is changed, thus mass exchange is carried out using the second perforated membrane, incorporated by reference to shown in Fig. 1,4,5.
The present invention is further described below with reference to embodiment 1 and embodiment 2.
Embodiment 1
The present embodiment carries freeze drying protectant (trehalose) in the device of red blood cell, and the first, second, and third chip uses
The rectangular organic glass chip that length is 12 centimetres, width is 7 centimetres.
It in the first passage of first chip lower surface setting, is carried out in the way of the distribution of S type, including vertical passage
With the interconnection for being transversely to the machine direction channel, the interconnection is connected to vertical passage.Through-hole 1 is cell suspending liquid
Entrance, through-hole 2 are the entrance of hypotonic solution.The S type mixer that setting length is about 12.7 centimetres in first passage inlet, makes
It obtains hypotonic solution and red blood cell suspension mixes herein, so that middle erythrocyte membrane pore-forming of the red blood cell in hypotonic solution, trehalose
Solution access apertures enters in red blood cell, flows through hypertonic point and enters the second chip second channel, mixes with hypertonic aqueous trehalose.?
The S type mixer that length is about 12.7 centimetres is arranged in second channel inlet, so that the mixed liquor of hypertonic solution and first passage
It mixes herein, so that red blood cell shrinkage in hypertonic solution of trehalose has been loaded, so that red blood cell is encapsulated by fenestra closing
In red blood cell.
Rectangular recess of a length of 12.5mm, depth that mass exchange area is made of 4 rectangular channels for 0.5mm, import
It is tree-shaped, every level-one four, 0.5 millimeter of rectangular channel interval with outlet；Its outlet is connected to the fourth lane, at outlet 6
For the outlet of fourth lane, hole 1,2,3,4 and 5 is through-hole.
First be arranged between first chip and the second chip and between the second chip and third chip is porous
Film, the first perforated membrane are rectangle pellosil, the pellosil with a thickness of 300 μm, the size of size and every layer of chip
Identical, first pellosil is completely covered on the lower surface of the first passage, another side and second pellosil on one side
Upper surface is completely covered, and the lower surface of second pellosil is bonded with the second channel upper surface of the lower layer chip, and described
A piece of and second pellosil separates the first passage and second channel；Same third piece and the 4th pellosil will be described
Third channel and fourth lane separate, and this will not be repeated here.
The second mass exchange film being arranged at second and third described chip mass exchange area, the second mass exchange film
Aperture be 0.45 μm, size is consistent with the size in the mass exchange area, and the one side of the second mass exchange film is covered completely
The mass exchange area of the third channel is covered, the mass exchange area of the fourth lane is completely covered in another side, and the second substance is handed over
It changes film to mix cell suspending liquid and the mass exchange liquid of fourth lane, it is extra quickly and efficiently to remove using mass exchange effect
Hemoglobin and impurity.
First chip, second and third chip are fastened by screw.
Embodiment 2
The load freeze drying protectant (trehalose) provided using embodiment 1 carries out red blood cell load sea in the device of red blood cell
Algae sugar, detailed process are as follows:
Red blood cell is collected, red blood cell is uniformly mixed with physiological saline, the cell that hematocrit ratio is 35 ± 5% is obtained and suspends
Liquid；
Load freeze drying protectant (trehalose) that the cell suspending liquid is provided from embodiment 1 is in the device of red blood cell
It is poured at the entrance 1 of the first passage, hypotonic aqueous trehalose is poured into from the entrance 2 of the first passage, cell is outstanding
Supernatant liquid is flowed with hypotonic aqueous trehalose along first passage, is uniformly mixed at S type mixer, and it is logical that mixed liquor flows into second
Road；Hypertonic aqueous trehalose is poured into from the entrance 3 of the second channel, mixed liquor and hypertonic aqueous trehalose are mixed in S type
It is uniformly mixed at clutch；The mass exchange area that mixed liquor gradually enters third channel (is handed over specific in the present embodiment for 4 grades of substances
Change system)；
The cell suspending liquid and mass exchange liquor of trehalose are by medical grade rubber hose respectively by 7 Hes of outlet
6 outflow loads freeze drying protectant (trehalose) are in the device of red blood cell；
The load freeze drying protectant (trehalose) that cell suspending liquid is provided in the embodiment of the present invention 1 is in the device of red blood cell
In it is stable after, take out sample with EP pipe at outlet 7 and with automatic clinical chemistry analyzer analysing haemoglobin concentration use enzyme
It marks instrument and analyzes trehalose concentration, test the survival rate of red blood cell and the load efficiency of the rate of recovery and trehalose respectively；Test knot
Fruit is that the load freeze drying protectant (trehalose) provided using the embodiment of the present invention 1 is carried out red blood cell in the device of red blood cell and born
Trehalose is carried, cell survival rate is 85% or more, and the rate of recovery is 76% or more and load efficiency is 30mM or more.
Load freeze drying protectant (trehalose) provided by the invention is led in the first chip in the micro-fluidic chip of red blood cell
The hypotonic trehalose of S type mixer and cell suspending liquid are crossed, is mixed later with the hypertonic aqueous trehalose of the second channel, by institute
The purpose that mass exchange area realizes fast automatic red blood cell load freeze drying protectant is stated, the mechanical damage and osmotic pressure of cell are reduced
Damage, improves the survival rate and the rate of recovery of cell.Device using this load freeze drying protectant (trehalose) in red blood cell has
Have the multiple functions such as freeze drying protectant load, removal freeze drying protectant, blood plasma separation, cell culture and drug screening, have compared with
Good convenience.
In addition, the above-mentioned definition to each element and method is not limited in the various specific structures mentioned in embodiment, shape
Shape or mode, those of ordinary skill in the art simply can be changed or be replaced to it.
It should be noted that the direction term mentioned in embodiment, such as "upper", "lower", "front", "rear", "left", "right"
Deng being only the direction with reference to attached drawing, the protection scope being not intended to limit the invention.Through attached drawing, identical element is by identical
Or similar appended drawing reference indicates.When may cause the understanding of the present invention and cause to obscure, conventional structure or structure will be omitted
It makes.And the shape and size of each component do not reflect actual size and ratio in figure, and only illustrate the content of the embodiment of the present invention.
In addition, in the claims, any reference symbol between parentheses should not be configured to limitations on claims.
Furthermore word "comprising" or " comprising " do not exclude the presence of element or step not listed in the claims.Positioned at member
Word "a" or "an" before part does not exclude the presence of multiple such elements.
The word of ordinal number such as " first ", " second ", " third " etc. used in specification and claim, with modification
Corresponding element, itself is not meant to that the element has any ordinal number, does not also represent the suitable of a certain element and another element
Sequence in sequence or manufacturing method, the use of those ordinal numbers are only used to enable an element and another tool with certain name
Clear differentiation can be made by having the element of identical name.
Similarly, it should be understood that in order to simplify the present invention and help to understand one or more of the various inventive aspects,
Above in the description of exemplary embodiment of the present invention, each feature of the invention is grouped together into single implementation sometimes
In example, figure or descriptions thereof.However, the method for the invention should not be construed to reflect an intention that i.e. required guarantor
Shield the present invention claims features more more than feature expressly recited in each claim.More precisely, as following
Claims reflect as, inventive aspect is all features for the single embodiment invented less than front.Therefore,
Thus the claims for following specific embodiment are expressly incorporated in the specific embodiment, wherein each claim itself
All as a separate embodiment of the present invention.
Particular embodiments described above has carried out further in detail the purpose of the present invention, technical scheme and beneficial effects
It describes in detail bright, it should be understood that the above is only a specific embodiment of the present invention, is not intended to restrict the invention, it is all
Within the spirit and principles in the present invention, any modification, equivalent substitution, improvement and etc. done should be included in guarantor of the invention
Within the scope of shield.
Claims (10)
1. a kind of device for red blood cell load freeze drying protectant, comprising:
First chip, lower surface have first passage, which includes multiple entrances and the first mixer；
Second chip, positioned at the lower section of first chip, upper surface has a second channel, the second channel include entrance and
Second mixer, lower surface have third channel, which includes mass exchange area and outlet；
Third chip, positioned at the lower section of second chip, upper surface has a fourth lane, the fourth lane include entrance,
Mass exchange area and outlet；
At least four first perforated membranes: the first surface of first first perforated membrane is bonded with the lower surface of first chip；
The first surface of second first perforated membrane is opposite with the second surface of first first perforated membrane, and second first porous
The second surface of film is bonded with the upper surface of second chip；The first surface of the first perforated membrane of third piece and second core
The lower surface of piece is bonded；The second surface phase of the first surface of 4th first perforated membrane and first perforated membrane of third piece
Right, the second surface of the 4th first perforated membrane is bonded with the upper surface of the third chip；
At least a piece of second perforated membrane, be arranged in second chip mass exchange area and third chip mass exchange area it
Between, first surface covers the mass exchange area of second chip, and second surface covers the mass exchange of the third chip
Area；
The first passage of first chip is connected to the second channel of second chip；The second channel of second chip
It is connected to third channel.
2. the apparatus according to claim 1, which is characterized in that thickness of the depth of the first passage less than the first chip
Degree；Thickness of the depth of the second channel less than the second chip；Thickness of the depth of the third channel less than the second chip；
The depth of the fourth lane is less than the thickness of third chip.
3. the apparatus according to claim 1, which is characterized in that
The first passage includes first entrance and second entrance, and for flowing into hypotonic solution, second entrance is used for first entrance
Red blood cell suspension is flowed into, first mixer is used to mix the hypotonic solution flowed into through first entrance and through second entrance stream
The red blood cell suspension entered；
The second channel includes third entrance, and for flowing into hypertonic solution, second mixer is for mixing to enter through third
The hypertonic solution that mouth flows into and the mixed liquor mixed through the first mixer, obtain the red blood cell suspension of load freeze drying protectant；
The fourth lane includes the 4th entrance and first outlet, and the 4th entrance is for flowing into isotonic solution；The isotonic solution
It flow to the mass exchange area of third chip by fourth lane, the red blood cell suspension of the load freeze drying protectant is via the
Two channels, third channel flow to the mass exchange area of the second chip, carry out mass exchange with the isotonic solution, and described the
One outlet is for the isotonic solution after flowing out exchange；
The third channel includes second outlet, for flowing out the red blood cell suspension of the load freeze drying protectant after exchanging；
The first passage of first chip is connected to the second channel of second chip, for making in the first passage
Mixed solution enters the second channel；The second channel of second chip is connected to third channel, for making described second
The mixed solution in channel enters the third channel.
4. the apparatus according to claim 1, which is characterized in that be arranged in two between second chip and third chip
There are multiple openings, second perforated membrane is arranged between first perforated membrane of two panels, covers institute on the first perforated membrane of piece
State multiple openings.
5. the apparatus according to claim 1, which is characterized in that the material of first chip, the second chip, third chip
For organic glass or dimethyl silicone polymer, first perforated membrane is silica gel perforated membrane, the second perforated membrane be poly (ether sulfone) film or
Polyvinylidene fluoride microporous filtering film.
6. the apparatus according to claim 1, which is characterized in that the face of first chip, the second chip and third chip
Product is between 70 square centimeters~150 square centimeters；The thickness of first chip, the second chip and third chip is between 5
Millimeter~10 millimeters between；
First perforated membrane with a thickness of 0.1 millimeter~0.5 millimeter, the aperture of first perforated membrane is 20 microns~50 micro-
Rice；The aperture of second perforated membrane is 0.1 micron~1.2 microns.
7. the apparatus according to claim 1, which is characterized in that first chip, the second chip and third chip are in rank
Ladder type distribution；The first passage and second channel use T-type tandem type distributed architecture, respectively include interconnection and perpendicular to
The vertical passage of interconnection, the interconnection are connected to vertical passage；First mixer, the second mixer are S-shaped
Mixer.
8. the apparatus according to claim 1, which is characterized in that the first passage, second channel and third channel are square
Connected in star structure, the width of rectangular recess are greater than the depth of groove.
9. the apparatus according to claim 1, which is characterized in that there are four miniature squares for tool centered on the mass exchange area
The rectangular recess of shape column, the width of rectangular recess are greater than the depth of groove, and the miniature rectangular column is used to support more than described second
Pore membrane.
10. a kind of side for carrying out red blood cell load freeze drying protectant using device as claimed in any one of claims 1-9 wherein
Method, comprising:
Red blood cell suspension is poured into from the first entrance of the first passage of the first chip of described device, by hypotonic solution from institute
The second entrance for stating the first passage of the first chip pours into, and red blood cell suspension and hypotonic solution are the first of first chip
It is uniformly mixed at mixer, mixed liquor flows into the second mixer of the second chip through first passage；
Hypertonic solution is poured into from the third inlet of the second channel of second chip, hypertonic solution and the mixing liquid stream
It is uniformly mixed to the second mixer of the second chip, and the second channel through the second chip, third channel flow to the second chip
Mass exchange area；
Isotonic solution is poured into from the 4th inlet of the fourth lane of the third chip, isotonic solution is along fourth lane stream
It is dynamic, it is flow to the mass exchange area of the third chip, carries out mass exchange with the mixed liquor in the mass exchange area of the second chip.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811146525.0A CN108949565A (en) | 2018-09-26 | 2018-09-26 | Device and method for red blood cell load freeze drying protectant |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811146525.0A CN108949565A (en) | 2018-09-26 | 2018-09-26 | Device and method for red blood cell load freeze drying protectant |
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| CN201811146525.0A Pending CN108949565A (en) | 2018-09-26 | 2018-09-26 | Device and method for red blood cell load freeze drying protectant |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112385645A (en) * | 2020-11-17 | 2021-02-23 | 广东省医疗器械研究所 | Upper chip and micro device for multi-stage adding of cell cryoprotectant |
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