CN102337207B - Microfluidic microbe two-dimensional suspension culture chip - Google Patents
Microfluidic microbe two-dimensional suspension culture chip Download PDFInfo
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- CN102337207B CN102337207B CN 201110316751 CN201110316751A CN102337207B CN 102337207 B CN102337207 B CN 102337207B CN 201110316751 CN201110316751 CN 201110316751 CN 201110316751 A CN201110316751 A CN 201110316751A CN 102337207 B CN102337207 B CN 102337207B
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Abstract
The invention discloses a microfluidic microbe two-dimensional suspension culture chip. The chip comprises more than one culture unit, wherein each culture unit comprises a culture layer, an elastic diaphragm layer and a driving layer which are overlapped; an annular closed culture channel loop is distributed on the culture layer, and the loop is communicated with a liquid inlet and a liquid outlet arranged on the chip; a plurality of linear driving channels are distributed on the driving layer, driving fluid is introduced into each driving channel according to a set time sequence, and each driving channel penetrates through the part above or below the culture channel loop and intersects with the two different selected regions of the loop; and through regulating the width, depth and quantity of the culture channels in the regions penetrated by the driving channels or arranging structures which are used for barring elastic diaphragms from deforming downwards in the culture channels, fluid flow is driven to carry out one-way movement at the same layer. According to the invention, few driving pipelines and external interfaces are used to drive culture fluid flow of multiple culture units, so that the quantity of the culture units in unit chip area is improved, and a large-scale parallel culture of microbes can be realized.
Description
Technical field
The present invention relates to a kind of biochip, relate in particular to a kind of microfluidic microbe two-dimensional suspension culture chip, it can realize that driving in the culture chamber of a plurality of formed objects liquid circulation with a small amount of driving raceway groove flows, and keeps the flow velocity should be basic identical.
Background technology
Existing high-throughput micro-current controlled cell cultivation chip there is no method and satisfies spawn culture requirement in the industrial fermentation.The topmost liquid fermenting mode of fermentation industry is submerged fermentation, namely apply in the somatic cells Uniform Dispersion liquid medium within that external force makes microorganism and carry out suspension culture, to promote absorption of nutrient ingredients and metabolite in time to disperse, reach the purpose of thalline or metabolite high yield.Industrial main by stirring rake or aerodynamic force in the fermentor tank, realize the thalline suspension culture.Yet be difficult to introduce corresponding mixing device in the micro-fluidic chip.Not only make miniature stirring rake very difficult, and small liquid culture system can't realize also that because of reasons such as evaporation, surface tension the air lift type circulation mixes.Micro-fluidic cultivation chip is mainly used in animal and people's cell cultures at present.Cell is attached to chip culturing room inwall, injects substratum in the chip and can realize cultivating, and lacks the nutrient solution mixed structure in the chip, therefore is not suitable for the suspension culture industrial microorganism.
At present carry out still report seldom of research that microbial suspension cultivates with micro-fluidic chip in the world wide, can be seen at present document and mainly contain following numerical example: a kind of four-way microreactor for the parallel fermentation of microorganism of (1) the 2005 year people such as Szita.N report, it can be used for colibacillary cultivation and fermentation, but this chip culturing room diameter is larger, stirring rake processing is installed also comparatively complicated, the room for promotion of cultivating element number is more limited, large (the Szita of manufacture difficulty, N., et al., Development of a multiplexed microbioreactor system for high-throughput bioprocessing. Lab on a Chip, 2005. 5 (8): p. 819-826.); A kind of multichannel microfluidic microbe culture apparatus of (2) the 2005 years people such as Groisman.A reports, nearly 340 of the cultivation unit of this device, but it lacks bacterium liquid mixed structure, only can leave standstill cultivation, thalline can't fully disperse in nutrient solution, fail to realize suspension culture truly, (the Groisman that differs greatly under thalli growth state and the condition of suspension culture, A., et al., A microfluidic chemostat for experiments with bacterial and yeast cells., Nature Methods, 2005. 2 (9): p. 685-689); (3) 2005 years Balagadd é. the microbial culture chip of a kind of six passages of the report such as FK, this chip comprises six independently looped pipeline cultivation unit, each unit volume 16 nL, integrated Pneumatic Micropump is used for driving the circulation of bacterium stream and mixes, above (the Balagadde of its continuously-running 500h, F.K., et al., Long-term monitoring of bacteria undergoing programmed population control in a microchemostat., Science, 2005. 309 (5731): p. 137-140).However, because integrated six unit only on the chip, cultivate the unit and take up room greatlyr, the element number room for promotion is very limited, and the pilot piping complexity is various, and using apart from the high-throughput bacterial screening still has a segment distance.
Therefore, all in all, the micro-fluidic chip that is used for the microbial suspension cultivation of having reported at present remains at repeating unit few, cultivate the unitary space area occupied large, lack effective mixing device, be difficult to the deficiencies such as array, can't satisfy the requirement of high-flux microorganism bacterial screening.
Summary of the invention
The object of the invention is to propose a kind of nutrient solution stream that can drive with a small amount of driving pipeline and external tapping a plurality of cultivations unit, thereby improve the quantity of cultivating the unit on the unit chip area, realize the microfluidic microbe two-dimensional suspension culture chip that the microorganism massive parallel is cultivated, and then overcome deficiency of the prior art.
For achieving the above object, the present invention has adopted following technical scheme:
A kind of microfluidic microbe two-dimensional suspension culture chip comprises more than one and cultivates the unit, it is characterized in that:
Each cultivates culture layer and driving layer that the unit comprises stacked setting, is provided with the elastic diaphragm layer between culture layer and the driving layer:
Be distributed with the closed raceway groove loop of cultivating of annular on the described culture layer, described cultivation raceway groove loop is communicated with fluid inlet and liquid outlet on being arranged on described chip;
Be distributed with linear driving raceway groove more than two on the described driving layer, each two ends that drive raceway groove all is communicated with the cultivation unit is outside, and all passes into actuating fluid by setting sequential in each driving raceway groove;
Postscript, each drives raceway groove and all passes above or below described cultivation raceway groove, and forms and intersect from two different selected positions on cultivating raceway groove;
And, among cultivating raceway groove and drive the raceway groove infall, all have at least the cultivation raceway groove of two infalls to have different effective widths and/or significant depth, thereby so that when all are cultivated raceway grooves and under the actuating fluid effect deformation occur with the elastic diaphragm that drives the raceway groove infall, the making a concerted effort of the side direction motivating force that nutrient solution in the cultivation raceway groove of each infall is produced be enough to drive the nutrient solution stream one-way circulation of cultivating in the raceway groove mobile;
Described effective width and significant depth refer to respectively can enter maximum width value and the maximum depth value of cultivating raceway groove when the elastic diaphragm of cultivating raceway groove and driving raceway groove infall is squeezed.
Preferably, described linear driving raceway groove parallel being distributed on the described driving layer arranged side by side more than two, its fluid inlet all is positioned at chip the same side, and respectively drive raceway groove with cultivate that raceway groove forms all intersect, the width of cultivation raceway groove that is positioned at each infall of this chip the same side all is less than or greater than the width of the cultivation raceway groove of the infall that is positioned at the chip opposite side.
Particularly preferred, described linear driving raceway groove parallel being distributed on the described driving layer arranged side by side more than two, its fluid inlet all is positioned at chip the same side, and respectively drive raceway groove with cultivate that raceway groove forms all intersect, the significant depth of cultivation raceway groove that is positioned at each infall of this chip the same side all is less than or greater than the significant depth of the cultivation raceway groove of the infall that is positioned at the chip opposite side.
Further, at least be positioned at chip phase the same side, each drives in raceway groove and the cultivation raceway groove of cultivating the infall that raceway groove forms and is distributed with supporter, described supporter comprises from cultivating the upwardly extending protuberance of trench bottom and/or being arranged at the horizontal support member of cultivating between the raceway groove top and bottom, the height of described protuberance is lower than cultivates raceway groove upper surface or concordant with it, and the diameter of described horizontal support member is less than cultivating channel depth.
Described horizontal support member comprises the complex root horizontal support post of parallel distribution.
As the preferred embodiment of another kind, this microfluidic microbe two-dimensional suspension culture chip comprises more than one cultivates the unit, it is characterized in that:
Each cultivates culture layer and driving layer that the unit comprises stacked setting, is provided with the elastic diaphragm layer between culture layer and the driving layer:
Be distributed with one on the described culture layer and main cultivate raceway groove and a group of branches is cultivated raceway groove, described main raceway groove and the branch of cultivating cultivates the raceway groove serial connection and forms the closed raceway groove loop of cultivating, and this cultivation raceway groove loop is communicated with fluid inlet and liquid outlet on being arranged on described chip,
This group of branches is cultivated raceway groove and is comprised two branches' cultivation raceway grooves that be arranged in parallel, and the two ends that raceway grooves are cultivated by these two branches are connected to form a duplexure with the described main raceway groove two ends of cultivating respectively;
Be distributed with linear driving raceway groove more than two on the described driving layer, each two ends that drive raceway groove all is communicated with the cultivation unit is outside, and all passes into actuating fluid by setting sequential in each driving raceway groove;
Postscript, each drives raceway groove and all passes above or below these two branches' cultivation raceway grooves and this master cultivation raceway groove, and intersects with these two branches' cultivation raceway grooves and this main selected position formation of cultivating on the raceway groove;
And, described branch cultivates raceway groove and has different effective widths and/or significant depth from the main raceway groove of cultivating, thereby so that in all main raceway grooves and branches of cultivating when cultivating raceway groove and under the actuating fluid effect, deformation occuring with the elastic diaphragms that drive the raceway groove infall, the making a concerted effort of the side direction motivating force that nutrient solution in the cultivation raceway groove of each infall is produced be enough to drive the nutrient solution stream one-way circulation of cultivating in the raceway groove loop mobile;
Described effective width and significant depth refer to respectively can enter maximum width value and the maximum depth value of cultivating raceway groove when elastic diaphragm is squeezed.
Particularly, the structure that raceway groove is cultivated by described two branches is identical, and width and/or the degree of depth of described branch cultivation raceway groove are all cultivated raceway groove less than the master.
As another preferred embodiment, this microfluidic microbe two-dimensional suspension culture chip comprises more than one cultivates the unit, it is characterized in that:
Each cultivates culture layer and driving layer that the unit comprises stacked setting, is provided with the elastic diaphragm layer between culture layer and the driving layer:
Be distributed with two on the described culture layer and main cultivate raceway grooves and two group of branches are cultivated raceway grooves, described main raceway groove and the branch of cultivating cultivates the raceway groove serial connection and forms the closed raceway groove loop of cultivating, and this cultivation raceway groove loop is communicated with fluid inlet and liquid outlet on being arranged on described chip,
Wherein, each group of branches is cultivated raceway groove and is comprised two branches' cultivation raceway grooves that be arranged in parallel, and the two ends that raceway grooves are cultivated by these two branches are connected to form a duplexure with two main ends of cultivating raceway grooves respectively;
Be distributed with linear driving raceway groove more than two on the described driving layer, each two ends that drive raceway groove all is communicated with the cultivation unit is outside, and all passes into actuating fluid by setting sequential in each driving raceway groove;
Postscript, each drives raceway groove and all cultivates from this two group of branches and pass above or below raceway groove, and cultivates selected position on raceway groove with each branch respectively and form and intersect;
And, all branches cultivate raceway grooves and cultivate raceway groove and all do not have different effective widths and/or significant depth between each branch's cultivation raceway groove on the same group with main, thereby so that when all branches' cultivation raceway grooves under the actuating fluid effect deformation occured with the elastic diaphragm that drives the raceway groove infall, the nutrient solution stream one-way circulation of making a concerted effort to be enough to drive in the cultivation raceway groove loop of the branch of each infall being cultivated the side direction motivating force that nutrient solution produces in the raceway groove flowed;
Described effective width and significant depth refer to respectively can enter maximum width value and the maximum depth value of cultivating raceway groove when elastic diaphragm is squeezed.
Preferably, the degree of depth and/or the width of all branches' cultivation raceway grooves are all cultivated raceway groove less than the master, and the structure of the cultivation raceway groove of the branch in same group is all identical, and the structure of interior branch's cultivation raceway groove is not different on the same group.
Particularly preferred, described microfluidic microbe two-dimensional suspension culture chip comprises a plurality of cultivations unit on parallel distribution and the same plane, and wherein, each raceway groove that respectively drives of cultivating in the unit is connected in series with respective drive raceway groove in the adjacent cultivation unit respectively.
Aforementioned culture layer and driving layer be at least by any one or two or more being combined to form in high molecular polymer, hydrogel, silicon chip, quartz, glass and the metallic substance, but be not limited to this.
Described elastic diaphragm layer is formed by the elastopolymer material, but is not limited to this.
The loop line, plane of the forms such as rectangle, circle can be selected in the described closed raceway groove loop of cultivating, but is not limited to this.
The interface of described fluid inlet, liquid outlet and driving raceway groove is arranged on top and/or the bottom of described chip.
Microfluidic microbe two-dimensional suspension culture chip of the present invention mainly is the principle work that utilizes peristaltic pump, that is: drive liquid or the gas that passes into certain pressure in the raceway groove by specific time sequence to every, cultivate the cultivation raceway groove and the infall that drives raceway groove of unit at each, described elastica is by specific time sequence generation deformation, and the structure of cultivating raceway groove by adjusting each infall, such as, adjust driven raceway groove and pass through the width of cultivating raceway groove in the zone, the degree of depth, quantity or the structure that hinders the downward deformation of elastica is set in cultivating raceway groove, adjust the deformation quantity of elastica, elastica is flowed to a side direction to the nutrient solution of making a concerted effort to promote to cultivate in the raceway groove of the side direction motivating force of nutrient solution generation in the cultivation raceway groove of each infall.
Particularly for the cultivation unit of same annular closed, cultivating raceway groove has two zones of intersection with the driving raceway groove, and the cultivation raceway groove of elastica in these two zones of intersection can be one, also can be divided into two or several branches raceway groove.If the cultivation raceway groove in each zone of intersection is one, then can adjusts respectively the degree of depth that this or two cultivate raceway groove, or cultivate in the raceway grooves at this or two supporting structure is set respectively; If arrange two in each zone of intersection with top set's raceway groove, but then these two degree of depth and/or the width with top set's raceway groove are adjusted respectively, or therein one or two so that supporting structure to be set respectively in top set's raceway groove.By such design, so that the liquid-driving power that elastica produces at these two regional deformation extruding cultivation raceway grooves is inconsistent, thereby promoting liquid flows at cultivation pipeline internal recycle, the microorganism that drives in the liquid is scattered in the whole liquid environment, and the driving raceway groove alternately operates the liquid stream that can drive in a plurality of cultivations unit that is passed through by it and circulates.
The present invention can get up a plurality of cultivation units in series and drives wherein liquid stream cyclic motion with a limited number of two above raceway grooves, drives the thalline motion, realizes suspension culture.In the chip of certain area, cultivating element number can significantly increase, and can only be 2 and drive raceway groove minimum, and in the situation that do not increase and drive raceway groove quantity, cultivating element number also can further increase.Thereby realize micro-fluidic hyperchannel microbial suspension cultivation, improve the batch cultivation efficient of chip, and, all cultivation raceway grooves are in same aspect among the present invention, make convenient, need not accurate aligning, and cultivate more tight that the unit can arrange, cultivation element number integrated in the unit surface is more.
Description of drawings
Figure 1A is the schematic top plan view of the first preferred embodiment micro-fluidic cell suspension culture chip of the present invention;
Figure 1B is the layered structure schematic top plan view of cultivating the unit shown in Figure 1A;
Fig. 1 C is that schematic top plan view is amplified in the part of Figure 1B dashed rectangle part
Fig. 1 D is the cross-sectional view of cultivating unit 1D along the line shown in Figure 1A;
Fig. 2 A is the schematic top plan view of the second preferred embodiment micro-fluidic cell suspension culture chip of the present invention;
Fig. 2 B is the first layer structure schematic top plan view of cultivating the unit shown in Fig. 2 A;
Fig. 2 C is that schematic top plan view is amplified in the part of Fig. 2 B dashed rectangle part
Fig. 3 A is the schematic top plan view of the third preferred embodiment micro-fluidic cell suspension culture chip of the present invention;
Fig. 3 B is the first layer structure schematic top plan view of cultivating the unit shown in Fig. 3 A;
Fig. 3 C is that schematic top plan view is amplified in the part of Fig. 3 B dashed rectangle part
Fig. 3 D is the cross-sectional view of cultivating unit 3D along the line shown in Fig. 3 A;
Fig. 4 A is the schematic top plan view of the 4th kind of preferred embodiment micro-fluidic cell suspension culture chip of the present invention;
Fig. 4 B is the first layer structure schematic top plan view of cultivating the unit shown in Fig. 4 A;
Fig. 4 C is the cross-sectional view of cultivating unit 4C along the line shown in Fig. 4 A;
Fig. 4 D is the cross-sectional view of cultivating unit 4D along the line shown in Fig. 4 A;
The assembly of each Reference numeral and indication thereof is respectively among the figure:
100,200,300,400 are in the chip one and cultivate the unit;
110,210,310,410 is the chip the first layer,
120 is the chip second layer,
130 is the 3rd layer of chip,
111,211,311,411 for being positioned at the cultivation tap drain road of chip the first layer;
121 for being positioned at branch's raceway groove of chip the first layer;
221 for being positioned at main split's raceway groove of chip the first layer
231 for being positioned at the inferior branch raceway groove of chip the first layer
321 for being positioned at the pillar stiffener of chip the first layer;
421 for being positioned at the shallow channel of chip the first layer;
112,212,312,412 for driving raceway groove;
113,213,313,413 is fluid inlet;
123,223,323,423 is liquid outlet;
114,214,314,414 for driving the raceway groove external tapping.
Embodiment
For deficiency of the prior art, this case contriver proposes technical scheme of the present invention through studying for a long period of time and putting into practice, and this technical scheme can adopt multiple embodiments.
But on the whole, the basic structure of this microfluidic microbe two-dimensional suspension culture chip is: this chip comprises more than one cultivates the unit, wherein, each cultivates culture layer and driving layer that the unit comprises stacked setting, is provided with the elastic diaphragm layer between culture layer and the driving layer:
Be distributed with the closed raceway groove loop of cultivating of annular on the described culture layer, described cultivation raceway groove loop is communicated with fluid inlet and liquid outlet on being arranged on described chip;
Be distributed with linear driving raceway groove more than two on the described driving layer, each two ends that drive raceway groove all is communicated with the cultivation unit is outside, and all passes into actuating fluid by setting sequential in each driving raceway groove;
Postscript, each drives raceway groove and all passes above or below described cultivation raceway groove, and form and intersect from two different selected positions on cultivating raceway groove, pass through width, the degree of depth, the quantity of cultivating raceway groove in the zone or the structure that hinders the downward deformation of elastica is set in cultivating raceway groove by adjusting driven raceway groove, and then drive the one-way movement of liquid stream in same aspect.
As a kind of preferred embodiment, among cultivating raceway groove and drive the raceway groove infall, all have at least the cultivation raceway groove of two infalls to have different in width and/or significant depth, thereby so that when all are cultivated raceway grooves and under the actuating fluid effect deformation occur with the elastic diaphragm that drives the raceway groove infall, the making a concerted effort of the side direction motivating force that nutrient solution in the cultivation raceway groove of each infall is produced be enough to drive the nutrient solution stream one-way circulation of cultivating in the raceway groove mobile.
Further, in this preferred version, described linear driving raceway groove parallel being distributed on the described driving layer arranged side by side more than two, its fluid inlet all is positioned at chip the same side, and respectively drive raceway groove with cultivate that raceway groove forms all intersect, the width of cultivation raceway groove that is positioned at each infall of this chip the same side all is less than or greater than the width of the cultivation raceway groove of the infall that is positioned at the chip opposite side.But obvious, each fluid inlet that drives raceway groove also can shift to install, and at this moment, those skilled in the art can need not according to the principle of work of peristaltic pump designing of any creative work can produce the channel structure that promotes the one-way flow of liquid stream.
Particularly preferred, described linear driving raceway groove parallel being distributed on the described driving layer arranged side by side more than two, its fluid inlet all is positioned at chip the same side, and respectively drive raceway groove with cultivate that raceway groove forms all intersect, the significant depth of cultivation raceway groove that is positioned at each infall of this chip the same side all is less than or greater than the significant depth of the cultivation raceway groove of the infall that is positioned at the chip opposite side.
Preferred, at least be positioned at chip phase the same side, each drives in raceway groove and the cultivation raceway groove of cultivating the infall that raceway groove forms and is distributed with supporter, described supporter comprises from cultivating the upwardly extending protuberance of trench bottom and/or being arranged at the horizontal support member of cultivating between the raceway groove top and bottom, the height of described protuberance is lower than cultivates the raceway groove upper surface, and the diameter of described horizontal support member is less than cultivating channel depth.
Described horizontal support member comprises the complex root horizontal support post of parallel distribution, but is not limited to this.
As the preferred embodiment of another kind, closure on the described culture layer is cultivated the raceway groove loop and is formed by a main cultivation raceway groove and group of branches cultivation raceway groove serial connection, this group of branches is cultivated raceway groove and is comprised two branches' cultivation raceway grooves that be arranged in parallel, the two ends that raceway groove is cultivated by these two branches are connected to form a duplexure with the described main raceway groove two ends of cultivating respectively, each drives raceway groove and all passes above or below these two branches' cultivation raceway grooves and this master cultivation raceway groove, and intersects with these two branches' cultivation raceway grooves and this main selected position formation of cultivating on the raceway groove;
And, described branch cultivates raceway groove and has different effective widths and/or significant depth from the main raceway groove of cultivating, thereby so that in all main raceway grooves and branches of cultivating when cultivating raceway groove and under the actuating fluid effect, deformation occuring with the elastic diaphragms that drive the raceway groove infall, the making a concerted effort of the side direction motivating force that nutrient solution in the cultivation raceway groove of each infall is produced be enough to drive the nutrient solution stream one-way circulation of cultivating in the raceway groove loop mobile;
In this scheme, preferred, the structure that raceway groove is cultivated by described two branches is identical, and width and/or the degree of depth of described branch cultivation raceway groove are all cultivated raceway groove less than the master.
As another preferred embodiment,
Closure on the described culture layer is cultivated the raceway groove loop and is formed by two main cultivation raceway grooves and two group of branches cultivation raceway groove serial connection, wherein, each group of branches is cultivated raceway groove and is comprised two branches' cultivation raceway grooves that be arranged in parallel, the two ends that raceway groove is cultivated by these two branches are connected to form a duplexure with two main ends of cultivating raceway groove respectively, each drives raceway groove and all cultivates from this two group of branches and pass above or below raceway groove, and cultivates selected position on raceway groove with each branch respectively and form and intersect; And, all branches cultivate raceway grooves and cultivate raceway groove and all do not have different effective widths and/or significant depth between each branch's cultivation raceway groove on the same group with main, thereby so that when all branches' cultivation raceway grooves under the actuating fluid effect deformation occured with the elastic diaphragm that drives the raceway groove infall, the nutrient solution stream one-way circulation of making a concerted effort to be enough to drive in the cultivation raceway groove loop of the branch of each infall being cultivated the side direction motivating force that nutrient solution produces in the raceway groove flowed.
Preferably, the degree of depth and/or the width of all branches' cultivation raceway grooves are all cultivated raceway groove less than the master, and the structure of the cultivation raceway groove of the branch in same group is all identical, and the structure of interior branch's cultivation raceway groove is not different on the same group.
Aforementioned effective width and significant depth refer to respectively can enter maximum width value and the maximum depth value of cultivating raceway groove when the elastic diaphragm of cultivating raceway groove and driving raceway groove infall is squeezed.
Postscript, this microfluidic microbe two-dimensional suspension culture chip comprise a plurality of cultivations unit on parallel distribution and the same plane, and wherein, each raceway groove that respectively drives of cultivating in the unit is connected in series with respective drive raceway groove in the adjacent cultivation unit respectively.
Aforementioned culture layer and driving layer be at least by any one or two or more being combined to form in high molecular polymer, hydrogel, silicon chip, quartz, glass and the metallic substance, but be not limited to this.
Described elastic diaphragm layer is formed by the elastopolymer material, but is not limited to this.
The described closed raceway groove loop of cultivating is preferably the rectangle loop line.
The interface of described fluid inlet, liquid outlet and driving raceway groove is arranged on top and/or the bottom of described chip.
But need to prove, because the present invention utilizes driven raceway groove to pass through cultivation channel width or the degree of depth or the raceway groove different amts in zone, the raceway groove of different structure can form resulting side force in various degree below the elastica extruding, thereby driving liquid stream one-way circulation flows, therefore, every driven raceway groove passes through the zone, cultivates the structure that raceway groove has different in width, the degree of depth or quantity or hinders the downward deformation of elastica, all can reach the purpose that drives the one-way movement of liquid stream in same aspect.
Below in conjunction with accompanying drawing and some preferred embodiments technical scheme of the present invention is further described.
Embodiment 1Consult Figure 1A ~ 1D, the present embodiment is comprised of the cultivation array that is distributed on the chip, this array comprises 4 cultivation unit 100 that are connected in series on the plane, each is cultivated the unit and has comprised cultivation tap drain road 111 and the branch's raceway groove 121 that is positioned at the first layer, cultivates the raceway groove two ends for these two sections and is interconnected, and consists of to overlook to be rectangular loop line, 1.5 millimeters of chip the first layer 110 thickness, the cultivation tap drain road 111 of the first layer is wide 100 microns, and dark 10 microns, long 6 centimetres; Article two, branch's raceway groove 121 is wide 50 microns respectively, and dark 10 microns, long 5 millimeters; Each cultivates the unit independently fluid inlet 113 and liquid outlet 123, and diameter is 2 millimeters, is used for injection and the discharge of liquid and culture; The shape size of each cultivation unit 100 is consistent, forms a line successively; Raceway groove top is the second layer 120, this layer is one deck elastic diaphragm, thick 20 microns, the first layer 110 and the 3rd layer 130 are separated, two parallel driving raceway grooves 112 are arranged for the 3rd layer 130, form micro-pump structure, widely be 100 microns, high 10 microns, horizontal neighbor distance 100um between raceway groove drives raceway groove 112 and cultivates tap drain road 111 from the first layer, branch's raceway groove 121 tops are passed through each and are cultivated unit 100, every drives raceway groove 112 two ends and all has external tapping 114, the 3rd layer 130 thick 1.5 millimeters of chips, the material of three chip layer is all selected polydimethylsiloxane, and each layer stacks gradually bonding.
Embodiment 2Consult Fig. 2 A ~ 2C, the present embodiment is comprised of the cultivation array that is distributed on the chip, this array comprises 4 cultivation unit 200 that are connected in series on the plane, and each is cultivated unit and has comprised the cultivation tap drain road 211 that is positioned at the first layer, two main split's raceway grooves 221, two branch's raceway grooves 231.1.5 millimeters of chip the first layer 210 thickness, the cultivation tap drain road 211 of the first layer is wide 100 microns, and dark 10 microns, long 5 centimetres; Article two, main split's raceway groove 221 is wide 100 microns respectively, and dark 10 microns, long 5 millimeters; Article two, time branch's raceway groove 231 is wide 50 microns respectively, and dark 10 microns, long 5 millimeters; Each cultivates the unit independently fluid inlet 213 and liquid outlet 223, and diameter is 2 millimeters, is used for injection and the discharge of liquid and culture; The shape size of each cultivation unit 200 is consistent, forms a line successively; Raceway groove top is the second layer 220, this layer is one deck elastic diaphragm, thick 20 microns, the first layer 210 and the 3rd layer 230 are separated, two parallel driving raceway grooves 212 are arranged for the 3rd layer 230, form micro-pump structure, widely be 100 microns, high 10 microns, horizontal neighbor distance 100um between raceway groove drives raceway groove 212 and cultivates main split's raceway groove 221 from the first layer, inferior branch passes through raceway groove 231 tops each and cultivates unit 200, every drives raceway groove 212 two ends and all has external tapping 214, the 3rd layer 230 thick 1.5 millimeters of chips, the material of three chip layer is all selected polydimethylsiloxane, and each layer stacks gradually bonding.
Embodiment 3Consult Fig. 3 A ~ 3D, the present embodiment is comprised of the cultivation array that is distributed on the chip, this array comprises 4 cultivation unit 300 that are connected in series on the plane, each is cultivated the unit and has comprised cultivation tap drain road 311 and 50 pillar stiffeners 321 that are positioned at the tap drain road that are arranged in the first layer, 1.5 millimeters of chip the first layer 310 thickness, the cultivation tap drain road 311 of the first layer is wide 100 microns, and dark 10 microns, long 6 centimetres; Support 321 high 10 microns, 30 microns of diameters, 70 microns at intercolumniation interval; Each cultivates the unit independently fluid inlet 313 and liquid outlet 323, and diameter is 2 millimeters, is used for injection and the discharge of liquid and culture; The shape size of each cultivation unit 300 is consistent, forms a line successively; Raceway groove top is the second layer 320, this layer is one deck elastic diaphragm, thick 20 microns, the first layer 310 and the 3rd layer 330 are separated, two parallel driving raceway grooves 312 are arranged for the 3rd layer 330, form micro-pump structure, widely be 100 microns, high 10 microns, horizontal neighbor distance 100um between raceway groove drives raceway groove 312 and cultivates tap drain road 311 from the first layer, pillar stiffener 321 tops are passed through each and are cultivated unit 300, every drives raceway groove 312 two ends and all has external tapping 314, the 3rd layer 330 thick 1.5 millimeters of chips, the material of three chip layer is all selected polydimethylsiloxane, and each layer stacks gradually bonding.
Embodiment 4Consult Fig. 4 A ~ 4D, the present embodiment is comprised of the cultivation array that is distributed on the chip, this array comprises 4 cultivation unit 400 that are connected in series on the plane, each is cultivated the unit and has comprised cultivation tap drain road 411 and the one section shallow channel 421 that is positioned at the first layer, 1.5 millimeters of chip the first layer 410 thickness, the cultivation tap drain road 411 of the first layer is wide 100 microns, and dark 10 microns, long 6 centimetres; Shallow channel 421 is wide 100 microns, and dark 5 microns, long 5 millimeters; Each cultivates the unit independently fluid inlet 413 and liquid outlet 423, and diameter is 2 millimeters, is used for injection and the discharge of liquid and culture; The shape size of each cultivation unit 400 is consistent, forms a line successively; Raceway groove top is the second layer 420, this layer is one deck elastic diaphragm, thick 20 microns, the first layer 410 and the 3rd layer 430 are separated, two parallel driving raceway grooves 412 are arranged for the 3rd layer 430, form micro-pump structure, widely be 100 microns, high 10 microns, horizontal neighbor distance 100um between raceway groove drives raceway groove 412 and cultivates tap drain road 411 from the first layer, shallow channel 421 tops are passed through each and are cultivated unit 400, every drives raceway groove 412 two ends and all has external tapping 414, the 3rd layer 430 thick 1.5 millimeters of chips, the material of three chip layer is all selected polydimethylsiloxane, and each layer stacks gradually bonding.
In the prior art, particularly cultivate chip as example take 6 passages of Balagadd é design, each Micropump fully independently drives liquid stream that each cultivates the unit in its structure, and each Micropump is by 3 gas pipelines and 3 external interfaces and external drive equipment connection.Cultivate the unit for 6 and need to make 6 independent Micropumps, comprise 18 driving pipelines.When driver element quantity improves, the quantity of integrated independent Micropump also must improve, the quantity of pipeline will improve 3 times, a large amount of driving raceway grooves not only makes the Design and Machining of chip and driving control system more complicated, and taken a large amount of chip areas, limited the further lifting of element number.And the present invention minimum can two raceway groove a plurality of cultivation units in series got up and drive wherein liquid stream cyclic motion, drive the thalline motion, realize suspension culture.In the chip of certain area, cultivate element number and can significantly increase (150 more than the unit), the chip (6) that is higher than Balagadd é, only be 2 and drive raceway groove, be less than the chip (driving 18 of raceway grooves) of Balagadd é, and drive raceway groove quantity in the situation that do not increase, cultivating element number also can further increase, thereby realizes micro-fluidic hyperchannel microbial suspension cultivation, improves the batch cultivation efficient of chip; And, the present invention all to cultivate raceway grooves be in same aspect, makes conveniently, need not accurate aligning, and cultivate more tight that the unit can arrange, the interior integrated cultivation element number of unit surface is more.
Below only be the introduction of inner characteristic of the present invention being carried out by concrete exemplary applications, the protection domain of inventing is not constituted any limitation.All employing equivalents or equivalence are replaced and the technical scheme of formation, all drop in the rights protection scope of the present invention.
Claims (12)
1. a microfluidic microbe two-dimensional suspension culture chip comprises more than one and cultivates the unit, it is characterized in that:
Each cultivates culture layer and driving layer that the unit comprises stacked setting, is provided with the elastic diaphragm layer between culture layer and the driving layer:
Be distributed with the closed raceway groove loop of cultivating of annular on the described culture layer, described cultivation raceway groove loop is communicated with fluid inlet and liquid outlet on being arranged on described chip;
Be distributed with linear driving raceway groove more than two on the described driving layer, each two ends that drive raceway groove all is communicated with the cultivation unit is outside, and all passes into actuating fluid by setting sequential in each driving raceway groove;
Postscript, each drives raceway groove and all passes above or below described cultivation raceway groove, and forms and intersect from two different selected positions on cultivating raceway groove;
And, among cultivating raceway groove and drive the raceway groove infall, all have at least the cultivation raceway groove of two infalls to have different effective widths or have different effective widths and significant depth, thereby so that when all are cultivated raceway grooves and under the actuating fluid effect deformation occur with the elastic diaphragm that drives the raceway groove infall, the making a concerted effort of the side direction motivating force that nutrient solution in the cultivation raceway groove of each infall is produced be enough to drive the nutrient solution stream one-way circulation of cultivating in the raceway groove mobile;
Described effective width and significant depth refer to respectively can enter maximum width value and the maximum depth value of cultivating raceway groove when the elastic diaphragm of cultivating raceway groove and driving raceway groove infall is squeezed.
2. microfluidic microbe two-dimensional suspension culture chip according to claim 1, it is characterized in that, described linear driving raceway groove parallel being distributed on the described driving layer arranged side by side more than two, its fluid inlet all is positioned at chip the same side, and respectively drive raceway groove with cultivate that raceway groove forms all intersect, the width of cultivation raceway groove that is positioned at each infall of this chip the same side all is less than or greater than the width of the cultivation raceway groove of the infall that is positioned at the chip opposite side.
3. microfluidic microbe two-dimensional suspension culture chip according to claim 1, it is characterized in that, described linear driving raceway groove parallel being distributed on the described driving layer arranged side by side more than two, its fluid inlet all is positioned at chip the same side, and respectively drive raceway groove with cultivate that raceway groove forms all intersect, the significant depth of cultivation raceway groove that is positioned at each infall of this chip the same side all is less than or greater than the significant depth of the cultivation raceway groove of the infall that is positioned at the chip opposite side.
4. microfluidic microbe two-dimensional suspension culture chip according to claim 3, it is characterized in that: be positioned at chip phase the same side at least, each drives in raceway groove and the cultivation raceway groove of cultivating the infall that raceway groove forms and is distributed with supporter, described supporter comprises by cultivating the upwardly extending protuberance of trench bottom and/or being arranged at the horizontal support member of cultivating between the raceway groove top and bottom, the height of described protuberance is lower than cultivates raceway groove upper surface or concordant with it, and the diameter of described horizontal support member is less than cultivating channel depth.
5. microfluidic microbe two-dimensional suspension culture chip according to claim 4, it is characterized in that: described horizontal support member comprises the complex root horizontal support post of parallel distribution.
6. a microfluidic microbe two-dimensional suspension culture chip comprises more than one and cultivates the unit, it is characterized in that:
Each cultivates culture layer and driving layer that the unit comprises stacked setting, is provided with the elastic diaphragm layer between culture layer and the driving layer:
Be distributed with one on the described culture layer and main cultivate raceway groove and a group of branches is cultivated raceway groove, described main raceway groove and the branch of cultivating cultivates the raceway groove serial connection and forms the closed raceway groove loop of cultivating, and this cultivation raceway groove loop is communicated with fluid inlet and liquid outlet on being arranged on described chip,
This group of branches is cultivated raceway groove and is comprised two branches' cultivation raceway grooves that be arranged in parallel, and the two ends that raceway grooves are cultivated by these two branches are connected to form a duplexure with the described main raceway groove two ends of cultivating respectively;
Be distributed with linear driving raceway groove more than two on the described driving layer, each two ends that drive raceway groove all is communicated with the cultivation unit is outside, and all passes into actuating fluid by setting sequential in each driving raceway groove;
Postscript, each drives raceway groove and all passes above or below these two branches' cultivation raceway grooves and this master cultivation raceway groove, and intersects with these two branches' cultivation raceway grooves and this main selected position formation of cultivating on the raceway groove;
And, described branch cultivates raceway groove and has different effective widths and/or significant depth from the main raceway groove of cultivating, thereby so that in all main raceway grooves and branches of cultivating when cultivating raceway groove and under the actuating fluid effect, deformation occuring with the elastic diaphragms that drive the raceway groove infall, the making a concerted effort of the side direction motivating force that nutrient solution in the cultivation raceway groove of each infall is produced be enough to drive the nutrient solution stream one-way circulation of cultivating in the raceway groove loop mobile;
Described effective width and significant depth refer to respectively can enter maximum width value and the maximum depth value of cultivating raceway groove when elastic diaphragm is squeezed.
7. microfluidic microbe two-dimensional suspension culture chip as claimed in claim 6 is characterized in that, the structure that raceway groove is cultivated by described two branches is identical, and width and/or the degree of depth of described branch cultivation raceway groove are all cultivated raceway groove less than the master.
8. a microfluidic microbe two-dimensional suspension culture chip comprises more than one and cultivates the unit, it is characterized in that:
Each cultivates culture layer and driving layer that the unit comprises stacked setting, is provided with the elastic diaphragm layer between culture layer and the driving layer:
Be distributed with two on the described culture layer and main cultivate raceway grooves and two group of branches are cultivated raceway grooves, described main raceway groove and the branch of cultivating cultivates the raceway groove serial connection and forms the closed raceway groove loop of cultivating, and this cultivation raceway groove loop is communicated with fluid inlet and liquid outlet on being arranged on described chip,
Wherein, each group of branches is cultivated raceway groove and is comprised two branches' cultivation raceway grooves that be arranged in parallel, and the two ends that raceway grooves are cultivated by these two branches are connected to form a duplexure with two main ends of cultivating raceway grooves respectively;
Be distributed with linear driving raceway groove more than two on the described driving layer, each two ends that drive raceway groove all is communicated with the cultivation unit is outside, and all passes into actuating fluid by setting sequential in each driving raceway groove;
Postscript, each drives raceway groove and all cultivates from this two group of branches and pass above or below raceway groove, and cultivates selected position on raceway groove with each branch respectively and form and intersect;
And, all branches cultivate raceway grooves and cultivate raceway groove and all do not have different effective widths and/or significant depth between each branch's cultivation raceway groove on the same group with main, thereby so that when all branches' cultivation raceway grooves under the actuating fluid effect deformation occured with the elastic diaphragm that drives the raceway groove infall, the nutrient solution stream one-way circulation of making a concerted effort to be enough to drive in the cultivation raceway groove loop of the branch of each infall being cultivated the side direction motivating force that nutrient solution produces in the raceway groove flowed;
Described effective width and significant depth refer to respectively can enter maximum width value and the maximum depth value of cultivating raceway groove when elastic diaphragm is squeezed.
9. microfluidic microbe two-dimensional suspension culture chip as claimed in claim 8, it is characterized in that, all branches cultivate the degree of depth and/or the width of raceway groove and all cultivate raceway groove less than the master, and the structure that raceway groove is cultivated by the branch in same group is all identical, and the structure of interior branch's cultivation raceway groove is not different on the same group.
10. according to claim 1 or 6 or 8 described microfluidic microbe two-dimensional suspension culture chips, it is characterized in that: described microfluidic microbe two-dimensional suspension culture chip comprises the parallel a plurality of cultivations unit that is distributed on the same plane, wherein, each raceway groove that respectively drives of cultivating in the unit is connected in series with respective drive raceway groove in the adjacent cultivation unit respectively.
11. according to claim 1 or 6 or 8 described microfluidic microbe two-dimensional suspension culture chips, it is characterized in that:
Described culture layer and driving layer are at least by any one or two or more being combined to form in high molecular polymer, hydrogel, silicon chip, quartz, glass, pottery and the metallic substance;
Described elastic diaphragm layer is formed by the elastopolymer material.
12. according to claim 1 or 6 or 8 described microfluidic microbe two-dimensional suspension culture chips, it is characterized in that: described fluid inlet, liquid outlet and the interface that drives raceway groove are arranged on top and/or the bottom of described chip.
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| CN102876562A (en) * | 2012-09-27 | 2013-01-16 | 大连大学 | Microfluidic chip system for culture and multiplication behavior research of marine microalgae |
| CN103865783B (en) * | 2012-12-13 | 2016-03-09 | 中国科学院苏州纳米技术与纳米仿生研究所 | Micro-fluidic strength of solution generation chip |
| WO2014082377A1 (en) * | 2012-11-28 | 2014-06-05 | 中国科学院苏州纳米技术与纳米仿生研究所 | Microfluidic chip |
| CN103834559B (en) * | 2012-11-28 | 2016-09-07 | 中国科学院苏州纳米技术与纳米仿生研究所 | Micro-fluidic chip |
| CN103897978B (en) * | 2012-12-26 | 2017-06-13 | 中国科学院苏州纳米技术与纳米仿生研究所 | Microfluidic microbe culture chip |
| CN104630061B (en) * | 2013-11-06 | 2017-02-08 | 中国科学院苏州纳米技术与纳米仿生研究所 | Micro-fluidic solution concentration generation and culture detection chip |
| CN103834554B (en) * | 2012-11-28 | 2016-01-27 | 中国科学院苏州纳米技术与纳米仿生研究所 | Microfluidic microbe cultivates detection chip |
| CN109946230B (en) * | 2019-02-26 | 2022-04-15 | 山东师范大学 | Microfluidic device for CTC high-throughput single-cell phenotypic analysis |
| CN114225982A (en) * | 2021-12-16 | 2022-03-25 | 青岛全诊生物技术有限公司 | Diaphragm type micro-fluidic control device |
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