CN101372663B - Vascular tissue engineering reactor having vas stretch and pulsating flow pouring functions - Google Patents
Vascular tissue engineering reactor having vas stretch and pulsating flow pouring functions Download PDFInfo
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- CN101372663B CN101372663B CN 200810102145 CN200810102145A CN101372663B CN 101372663 B CN101372663 B CN 101372663B CN 200810102145 CN200810102145 CN 200810102145 CN 200810102145 A CN200810102145 A CN 200810102145A CN 101372663 B CN101372663 B CN 101372663B
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- 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
- C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
- C12M29/12—Pulsatile flow
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- 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
- C12M21/00—Bioreactors or fermenters specially adapted for specific uses
- C12M21/08—Bioreactors or fermenters specially adapted for specific uses for producing artificial tissue or for ex-vivo cultivation of tissue
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- 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
- C12M27/00—Means for mixing, agitating or circulating fluids in the vessel
- C12M27/10—Rotating vessel
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- 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
- C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
- C12M29/10—Perfusion
Abstract
The invention relates to a vascular tissue engineering reactor which is characterized by comprising intravascular perfusion liquid storage bottles (101) which are connected with each other in sequence by pipelines, a pulsation source (102) which is taken as an intravascular perfusion liquid driving device, a culture cavity inlet pipeline (202) of an intravascular perfusion circuit, and a vascular tissue culture cavity (107), wherein, one end of an inlet pipeline (104) of the culture cavity enters the vascular tissue culture cavity (107), and is connected with one end of a vascular tissue (108) to be cultured so as to cause the culture solution from the perfusion liquid storage bottle (101) to flow into the vascular tissue (108). The reactor further comprises a culture cavity outlet pipeline (204) of the intravascular perfusion circuit, one end of the culture cavity outlet pipeline (204) enters the vascular tissue culture cavity (107), and is connected with the other end of the vascular tissue (108) to be cultured so as to export the culture solution from the inner part of the vascular tissue (108).
Description
Technical field
The present invention relates to cell cultures, field of tissue engineering technology, more particularly relate to a kind of vascular tissue engineering reactor with blood vessel stretching and pulsation function.
Background technology
Up to now, autotransplantation, allogeneic blood vessel, heterogenous blood vessel and synthetic blood vessel all can not become ideal arteries surrogate (the particularly following blood vessel of 6mm bore), but have brought hope with arteries organizational project bioreactor for constructing and research organization's through engineering approaches arteries for this field in recent years.At present, the research contents of arteries used in tissue engineering bio-reactor mainly comprises:
1. vascular tissue is realized and even, the high-density inoculation of control cell in support: the direct filling type bioreactor of discovering in recent years is being better than non-direct filling type bioreactors such as static state, rotation stirring-type aspect cell inoculation density and the homogeneity, this technology has been applied to myocardial cell, vascular tissue and liver cell organizational project
2. improve the mass transfer situation: for vascular tissue, the rotary bio-reactor of wall provides certain low shear-stress by dynamic rotation Laminar Flow for cell, improved mass transfer situation culture effect preferably and be better than rotating-filling rate of the rotary bio-reactor of stirring type bioreactor wall, the problems such as balance of the shearing stress size that pair cell applies, cytotrophy thing and metabolite mass transfer all can exert an influence to culture effect, therefore need be at parameters such as specific organizational controls, adjusting filling rates, with the mass transfer effect that obtains to optimize.
3. in the intravascular tissue engineering cultivation, apply suitable mechanical force, controlling arterial vascular engineering tissue makes up: a large amount of fluid shear stress that studies show that have the influence of highly significant to the growth of vascular endothelial cell, periodically mechanical extension can improve the organizational structure's performance of the smooth muscle cell structure that is planted on the polymeric stent material and the expression of elastin, and radial pulsation stress can improve the structural strength of engineering blood vessel.Therefore, in engineered culturing process, apply mechanical loading, can directly promote cell specific vegetative period to multi-functional differentiation, promote the structure of engineering tissue.
Boris A.Nasseri etc. has designed a kind of engineering blood vessel bio-reactor and has been used for cell inoculation and cultivation (Dynamic Rotational Seeding and CellCulture System for Vascular Tube Formation.TissueEngineering 2003; 9 (2): 291-299.): provide rotary power with hybrid heater for the blood vessel cultivation, produce the wall rotation of nutrient solution around the rotation of hybrid heater central shaft, improve mass transfer with respect to vessel wall by the blood vessel culture chamber; Reactor adopts dabbling mode in the blood vessel.
Ralf Sodian etc. has designed a kind of engineering blood vessel bio-reactor and has been used for the perfusion inoculation of blood vessel and cultivates (Tissue-Engineering Bioreactors:A NewCombined Cell-Seeding and Perfusion System for VascularTissue Engineering.Tissue Engineering 2002; 8 (5): 863-870.): produce pulsating flow with pneumatic mode extruding nutrient solution storage chamber silicone skirt, carry out pulsating flow pouring and cultivate, cell inoculation is combined with the pulsating flow pouring cultivation, dynamically inoculation improves cell distribution; Perfusion pulsating flow in the blood vessel; Reactor adopts dabbling mode in the blood vessel, and culture chamber does not have the wall rotation.
Chrysanthi Williams etc. has designed and a kind ofly provides power by peristaltic pump, engineering blood vessel bio-reactor that can perfusion inside and outside the blood vessel is used for small-caliber vascular and cultivates, outer perfusion improves the cytotrophy situation, interior perfusion provides shear-stress and pulsating flow surrounding, and culture chamber does not have wall rotation (Perfusion Bioreactor for SmallDiameter Tissue-Engineered Arteries.Tissue Engineering2004; 10 (5-6): 930-941.).
Yuji Narita etc. has designed a kind of vascular tissue engineering reactor (Novel Pulse Duplicating Bioreactor System forTissue-Engineered Vascular Construct.Tissue Engineering2004 that simulates physiological pulsating flow; 10 (7-8): 1224-1233.): the to-and-fro movement by sacculus formula chamber promotes the nutrient solution in the conformability chamber, produces pulsating flow, variable valve is set before and after culture chamber and has pulsating waveform under the liquid storage cylinder simulation physiological status of check valve; Reperfusion mode is perfusion in the blood vessel, no wall rotation.
Satish, C.Muluk etc. have designed the vascular reaction device that the enough stretching motors of a kind of energy load tensile stress and load torsional stress with micro-stepping motors, provide pulsating flow by program-controlled valve, adopt dabbling mode in the blood vessel, no wall rotation (Enhancementof tissue factor expression by vein segments exposed tocoronary arterial hemodynamics.Journal of vascularsurgery:official publication, the Society for VascularSurgery[and] International Society for CardiovascularSurgery, North American Chapter 1998; 27 (3): 521-527).
Craig A.Thompson etc. has designed a kind of vascular tissue engineering reactor (A Novel Pulsatile, Laminar Flow Bioreactorfor the Development of Tissue-Engineered VascularStructures.Tissue Engineering 2002 that simulates physiological pulsating flow; 8 (6): 1083-1088.): provide pressurized air flow to promote nutrient solution with ventilator and flow, regulate simulation arteries diastolic pressure by vacuum breaker, with the flow direction of check valve controlled liq in the loop, simulated blood vessel pulsating waveform as pulsation source; Perfusion in the blood vessel, no wall rotation.
In sum, there is bigger defective in existing vascular tissue engineering reactor: the one, do not think over factors such as flow impedance, conformability (elasticity of vessel wall is surge capability both), resistance, inertial flow, and can't provide the nearly physiology flowing environment that is similar to intra-arterial blood pulses stream mode to the simple analog of vascular flow dynamics environment; The 2nd, can't provide the periodicity axial tension of approximate physiological status, mechanical force such as stretching, distortion load radially simultaneously for vascular tissue; The 3rd, most modes that adopt no wall rotation, at cell evenly, be still waiting improvement aspect high-density inoculation and the mass transfer.Therefore, press for development and can load arteries simultaneously and cultivate required multiple mechanical environment, help cell evenly, the high-density inoculation, help mass transfer, have the bio-reactor of good Modulatory character.
Summary of the invention
The present invention is directed to the body interior mechanics environment of arteries tissue growth, the various embodiments of the vascular tissue engineering reactor with spinfunction are provided, these embodiments have excellent mass transferring performance, can cultivate for arteries nearly physiological pulsating flow surrounding is provided.
In these embodiments some can also be as the construction platform with multi-purpose reactor, these functions make it possible to loading classes simultaneously and are similar to arteries is subjected under the physiological status periodicity axial tension, mechanical loading such as stretching, distortion radially, and above-mentioned mechanical loading has good Modulatory character; Vascular tissue's horizontal rotation can be provided simultaneously, make reactor have excellent mass transferring performance, specifically comprise:
1, can drive blood vessel under the situation of culture chamber internal rotation by vascular tissue's rotating machine, realize inside and outside while or independent perfusion culture liquid, provide and to have carried out inside and outside while or independent dabbling equipment scheme;
2, can realize pulsing function (require inside and outside perfusion by two independently the nutrient solution loop finish);
3, can realize axial push-and-pull function, at least one in inlet pipe and the outlet pipe made axially reciprocating under the driving of axial drive means.
An object of the present invention is to provide a kind of multi-modal arteries tissue engineering reactor, the organizational project arteries that utilizes this reactor can carry out multiple diameter and length is cultivated, also can carry out vascular cell, the biological research of vascular tissue, its characteristics are:
1. adopt new arteries tissue engineering reactor principle of design: simulation arterial blood mobile conformability and resistance to flow on flow circuits produce nearly physiological pulsating flow; Can simulate ripple frequency, pressure and the flow waveform of different artery segments, simulation hypertension, shearing force, hemodynamic situation such as low shear-stress;
2. simultaneously loading classes is similar to arteries is subjected under the physiological status periodicity axial tension, mechanical loading such as stretching, distortion radially, and above-mentioned mechanics loads has good Modulatory character;
3. can carry out vascular tissue's rotation with adjustable rotating speed, inside and outside all can the realization of its medium vessels poured into, and makes reactor have excellent mass transferring performance.
The invention discloses a kind of a kind of infinite embodiment of vascular tissue engineering reactor, this reactor has following feature:
Reactor has perfusion and two perfusions of blood vessel outer filling loop in the blood vessel, and mechanical loading loads and proofing unit is positioned on the loop, and the observing and controlling part is made up of concentrator, small signal amplifier, driving mechanism, treater and indicating meter.
One concrete but among the infinite embodiment, liquid storage bottle is provided with the sterile air interchanger, the pH meter interface is arranged; The material of liquid storage bottle for can the withstand high temperatures disinfectant, the glass that does not have bio-toxicity, stainless steel, plastics, polycarbonate; The capacity of liquid storage bottle is 0.2L-2L;
As concrete but infinite embodiment, liquid driving device is peristaltic pump, linear electric motors and/or pulsation source, can realize flowing environment such as steady state flow, simple pulsating flow, nearly physiological pulsating flow by industrial computer controlling flow moving curve.
One concrete but among the infinite embodiment, peristaltic pump provides steady state flow, flow range is 0-1000ml/ minute, pressure is 0-250mmHg; In another specific embodiment, linear electric motors provide simple pulsating flow, and ripple frequency is 0-200 time/minute, and flow range is 0-1000ml/ minute, and pressure is 0-250mmHg; Pulsation source provides nearly physiological pulsating flow, and pulsation source is made of pulsation chamber, the linear electric motors that two ends are equipped with unidirectional non-return valve.
The pulsation chamber is the volume fixed closed chamber of full of liquid, the below of closed chamber links to each other with linear electric motors by Air-tight piston, closed chamber links to each other with the reactor pipeline of upstream and downstream by its central elastic hose, in the upstream and downstream exit of flexible pipe a unidirectional non-return valve is arranged respectively; The material of elastic hose is resilient organic materials.
One concrete but in the infinite embodiment, respectively there is a liquid dispenser at vascular tissue culture chamber two ends, connect perfusion upstream and downstream pipeline and vascular tissue's culture in the blood vessel with removably; Also respectively there is an outlet at vascular tissue culture chamber two ends, link to each other with blood vessel outer filling pipeline with removably respectively.
As concrete but infinite embodiment, the material of vascular tissue's culture chamber for can the withstand high temperatures disinfectant, the glass that does not have bio-toxicity, stainless steel, plastics, polycarbonate, be shaped as right cylinder or symmetric polyhedron, length is for example 10-50cm, and capacity is for example 50-500ml; Vascular tissue's culture chamber keeps cultivating cavity airtight by gasket and bolt, but the material of gasket and bolt is the organic and inorganic material of withstand high temperatures disinfectant.
As concrete but infinite embodiment, the volume of priming line is for example 100-500ml in the reactor blood vessel, and the volume of outer filling pipeline is for example 100-800ml.
As concrete but infinite embodiment, liquid dispenser is positioned at vascular tissue's culture chamber, the container that outlet is all arranged for two ends, its end that links to each other with perfusion upstream and downstream pipeline in the reactor blood vessel has an outlet, the end that links to each other with the vascular tissue culture has for example 1-6 outlet, liquid in the reactor blood vessel in the priming line is entered by the upstream extremity of upstream liquid divider, flowing out dispersion by downstream end enters in each vascular tissue's culture, flow out by the upstream extremity inflow of downstream divider and from its downstream end again, compile priming line in the intravasation.
As concrete but infinite embodiment, one of liquid dispenser is fixing vertically, and another can move back and forth in vascular tissue's culture chamber vertically.
As concrete but infinite embodiment, the liquid dispenser material for can the withstand high temperatures disinfectant, the glass that does not have bio-toxicity, stainless steel, plastics, polycarbonate, the diameter of its outlet is for example 1-12mm.
As concrete but infinite embodiment, linear electric motors provide that static state is drawn, stress, can provide also that cycle dynamics draws, stress.
As concrete but infinite embodiment, stepper-motor drives vascular tissue's rotary transmission gear rotation.
As concrete but infinite embodiment, reactor is used for the arterial vascular cultivation of organizational project, and analog approximation in the overall waveform of physiological pulsating flow, secondaries, amplitude with the time mutually, haemodynamics environment such as the senior executive internal pressure of analogy under pathological state, shearing force, low shear-stress; Be used for simultaneously or the analogy periodicity axial tension that arteries is subjected under physiological status, mechanical loading such as stretching, distortion radially separately.
As concrete but infinite embodiment, the to-and-fro movement of linear electric motors is penetrated the process that blood is gone into aorta to the overflow mould pseudocardia that the pulsation chamber produces, by regulating linear electric motors, conformability setter and dragulator, adjust pulse waveform, pressure and flow range and the frequency of beating within the specific limits, ripple frequency, pressure and flow waveform to the different artery segments of blood vessel simulation cultivated, simulation hypertension, shearing force, hemodynamic situation such as low shear-stress.
As concrete but infinite embodiment, stepper-motor, vascular tissue's rotary transmission gear constitute swivel arrangement; Wherein vascular tissue's rotary transmission gear has two groups, lays respectively at vascular tissue culture chamber two ends, is coupled with liquid dispenser.
As concrete but infinite embodiment, vascular tissue engineering reactor of the present invention is used for the arterial vascular cultivation of organizational project, arteries tubing comprises through taking off the animal blood vessels that cell is handled, tubing that constitutes by natural materialss such as collagen, silk fiber, wool fibers and the tubing that constitutes by superpolymer such as PLGA, PLA, PLG, sodium alginate, tetrafluoroethylene, blood vessel diameter is for example between the 1-12mm, length of vessel is for example between the 10-30cm, and the cell on the blood vessel tubing comprises vascular endothelial cell, vascular smooth muscle cell and adventitia inoblast.
As concrete but infinite embodiment, the whole priming line of vascular tissue engineering reactor of the present invention is kept 37 ℃, 5-15% CO by putting into the animal cell culture case
2, the culture condition of 95% relative humidity.
Reactor assembly of the present invention is installed, convenient disassembly; Whole reactor, comprise that perfusion channel pipeline and joint are detachable, can sterilize that exemplary conditions for sterilization is for for example: 130 ℃, 3 normal atmosphere, 1 hour time.
Vascular tissue engineering reactor of the present invention, compared following beneficial effect with pre-existing reactors:
1. vascular tissue engineering reactor of the present invention concrete but infinite embodiment, overcome the arteries tissue engineering reactor of using always and can't simulate the impedance characteristics such as conformability, inertial flow and resistance to flow of arteries blood flow, the shortcoming that is similar to intra-arterial blood pulses stream environment can't be provided, can on flow circuits, simulate impedance characteristics such as arterial blood mobile conformability, inertial flow and resistance to flow, can on flow circuits, simulate the pressure and the flow pulse wave of nearly physiological pulsating flow, produce nearly physiological pulsating flow; Can adjust pulse waveform, pressure and flow range within the specific limits, reach ripple frequency, simulate ripple frequency, pressure and the flow waveform of different artery segments, simulation hypertension, shearing force, hemodynamic situation such as low shear-stress;
2. in conduct of vascular tissue engineering reactor of the present invention but among the infinite embodiment, can on the blood vessel culture simultaneously or separately loading classes be similar to arteries is subjected under the physiological status periodicity axial tension, mechanical loading such as stretching, distortion radially, above-mentioned mechanical loading has good Modulatory character;
3. concrete but among the infinite embodiment of vascular tissue engineering reactor of the present invention, reactor culturing room partly is spirotheca-direct fill-up mode, can carry out vascular tissue's rotation with regulatable rotating speed, inside and outside all can the realization of its medium vessels poured into, and makes reactor have excellent mass transferring performance;
4. vascular tissue engineering reactor of the present invention a kind of concrete but infinite embodiment, both can be used for cultivating the arteries tissue, also can be used as research vascular cell, the biology of tissue and the instrument of mechanical property, have bigger popularizing application prospect and bigger potential economic results in society.
Description of drawings
Fig. 1 has shown the embodiment of a kind of indefiniteness of the present invention, is used to illustrate the device setting and the principle of interior perfusion loop pulsation of the present invention.
Fig. 2 has shown a further concrete non-limiting embodiment of the present invention, has wherein further comprised the part of the vascular tissue that the culture chamber 107 that is used for stretching is cultivated.
Fig. 3 has shown a further concrete non-limiting embodiment of the present invention, has wherein further comprised the part of the rotation of the vascular tissue 108 that realization is cultivated.
Fig. 4 has shown a further concrete non-limiting embodiment of the present invention, has wherein further comprised the part of the outer filling of the vascular tissue 108 that realization is cultivated.
Embodiment
Shown among Fig. 1 that concrete Fig. 1 of the present invention has shown the embodiment of a kind of indefiniteness of the present invention, be used to illustrate the device setting and the principle of interior perfusion loop pulsation of the present invention.As shown in Figure 1, as the embodiment of an indefiniteness of the present invention, in blood vessel, between perfusion liquid storage bottle 101 and the vascular tissue's culture chamber 107, be connected with pulsation source 102, first dragulator 105, the first conformability setter 106 in turn by pipeline.
As shown in Figure 1, pulsation source 102 of the present invention comprises pulsation chamber 103, passes the elastic hose 104 in pulsation chamber 103, the unidirectional non-return valve 111 in upstream that is arranged on the upstream port place of elastic hose, the unidirectional non-return valve 114 in downstream, the packed-piston 113 of downstream port that are arranged on elastic hose 104 and the linear electric motors 112 that are used to drive packed-piston 113.Pulsation chamber 103 is volume fixed closed chamber of a full of liquid.And elastic hose 104 has constituted the part that pulsation chamber 103 is passed in the perfusion loop in the blood vessel.The to-and-fro movement of linear electric motors 112 by piston 113, and produces squeezing action to the liquid that pulsation is full of in the chamber 103, this extruding and then act on the nutrient solution in the elastic hose 104, thus in blood vessel, produce corresponding pulsating flow in the perfusion loop.
As a kind of preferred but infinite embodiment, can make this pulsating flow simulation cardiac ejection go into the fluctuation of aorta, and can regulate ripple frequency, flow and the pressure of pulsating flow within the specific limits.Unidirectional non-return valve 111,114 is used to guarantee be unidirectional pulsating flow from the effusive nutrient solution stream of pulsation source.
One first dragulator of label 105 expressions.Dragulator is the mechanic adjustment unit that is connected on the pipeline, variable valve for example, and it is used for by regulating the flow of tube chamber size adjustment loop liquid, and is accompanied by the adjusting of perfusion pressure.
One first conformability setter of label 106 expressions.The conformability setter is the setting device that is connected on the pipeline, is used to regulate because the variation of the liquid capacity that pressure change caused.
One second conformability setter of label 109 expressions, one second dragulator of label 110 expressions.
First and second dragulators 105,110 respectively are used for regulating the perfusion pressure of nutrient solution of culture chamber 107 and waveform, the wave amplitude of nutrient solution perfusion pressure change.The first and second conformability setters 106,109 respectively are used for regulating the inertial flow of the nutrient solution of culture chamber.First and second dragulators 105,110 and the first and second conformability setters 106,109 be used for regulating jointly respectively with the overall waveform that obtains to be similar to physiological pulsating flow, secondaries, amplitude with the time mutually, acquisition is similar to hypertensive senior executive's internal pressure, haemodynamics environment such as shearing force, or the hemodynamic situation of simulation arteries when hanging down shear-stress.
Fig. 2 has shown a further concrete non-limiting embodiment of the present invention.Compare with embodiment shown in Figure 1, the embodiment of Fig. 2 has further comprised the part of the vascular tissue that the culture chamber 107 that is used for stretching is cultivated.
As shown in Figure 2, priming line upstream support in blood vessel of label 201 expressions, perfusion loop culture chamber inlet ductwork in the label 202 expression blood vessels, label 203 expression culture chamber sealing plugs, perfusion loop culture chamber export pipeline in the label 204 expression blood vessels, label 206 expression stretching motor pull bars, perfusion downstream, loop support in the label 205 expression blood vessels, label 207 expression stretching motors.
In the embodiment as a kind of indefiniteness, combining between the sealing plug 203 in culture chamber export pipeline 204 and downstream is slidably, the reciprocal stretching of stretching electric motor driving bar 206 drives and acts on the culture chamber export pipeline 204, thereby drive export pipeline 204 along axially reciprocating, thereby realize reciprocal stretching the vascular tissue 108 in cultivating.
By embodiments of the present invention as shown in Figure 2, pulsating flow of the nutrient solution in the vascular tissue 108 in can realizing simultaneously cultivating (being the pulsation of nutrient solution pressure) and vascular tissue 108 are along axial reciprocal stretching.
Should be understood that the set-up mode of stretching motor 207 shown in Figure 2 is not unique; Stretching motor 207 can be set at the upstream side of culture chamber 107 equally, and/or be coupled with culture chamber inlet ductwork 202.
Further, stretching motor 207 neither be realized unique embodiment of the to-and-fro movement generating unit of vascular tissue 108, and it can be substituted by other forms of device, as motor-driven crank-link mechanism, hydro-cylinder etc.
These distortion embodiments all belong to scope of the present invention.
Fig. 3 has shown a further concrete non-limiting embodiment of the present invention; Compare with embodiment shown in Figure 2, further comprised the part of the rotation of the vascular tissue 108 that realization is cultivated in the embodiment of Fig. 3.
The downstream end of perfusion loop culture chamber inlet ductwork 202 enters into vascular tissue's culture chamber 107 in the blood vessel.Label 305 is represented, it is an optional culture chamber upstream liquid divider, it links to each other with the downstream end of inlet ductwork 202, and the upstream extremity of many vascular tissues 108 to be cultivated is enclosed within on this upstream liquid divider, cultivates when realizing many vascular tissues.
The downstream end of vascular tissue 108 to be cultivated is enclosed within downstream liquid divider 306.Downstream divider 306 links to each other with the upstream extremity of perfusion loop culture chamber export pipeline 204 in the blood vessel, and the downstream end of culture chamber export pipeline 204 is reaching outside the culture chamber 107, and by priming line downstream coupling 309 in the blood vessel be connected to blood vessel in the pipeline of perfusion liquid storage bottle 101 link to each other, flow back to the road thereby form the interior perfusion fluid of a complete blood vessel.Downstream coupling 309 has been realized rotating culture chamber export pipeline 204 and has been connected to being tightly connected between the pipeline that does not rotate that pours into liquid storage bottle 101 in the blood vessel.
Among Fig. 3, label 203 expression sealing plugs, be used to make inlet ductwork 202 and export pipeline 204 in the mode of sealing into and out of culture chamber 107.
In the indefiniteness embodiment shown in Figure 3, also comprise priming line upstream support 201 and downstream support 205 in the blood vessel, they are respectively applied in rotating mode and support and/or keep culture chamber inlet ductwork 202 and export pipeline 204.
In infinite embodiment shown in Figure 3, vascular tissue's rotational drive motor of label 310 expressions.The rotation axis of motor 310 and upstream driving gear set 304 and downstream driving gear set 307 are coupled, and do to rotate synchronously to drive driving gear set 304 and 307.Driving gear set 304 also is coupled with culture chamber inlet ductwork 202, and driving gear set 307 also is coupled with culture chamber export pipeline 204, thereby the rotation of driving gear set 304 and 307, driven the rotation of culture chamber inlet ductwork 202 and culture chamber export pipeline 204 respectively, and the rotation of the rotation of culture chamber inlet ductwork 202 and culture chamber export pipeline 204 is synchronized with each other, thereby causes the rotation of waiting to cultivate vascular tissue 108 that is arranged between inlet ductwork 202 and the export pipeline 204.
At this, this mode that back and forth moves radially that downstream driving gear set 307 is held with its rotation coupled export pipeline 204 can have multiple.
The first, gear direct-coupled with it and absorbs back and forth moving radially of export pipeline 204 with the radially sliding engagement between the gear of downstream driving gear set 307 along axially interfixing in export pipeline 204 and the downstream driving gear set 307.For this reason, a kind of possibility is, the thickness of one of two gears of the engagement that takes place in the gear unit 307 to slide obviously greater than another, thereby avoided because the engagement of the slip between the gear causes the possibility of engagement disengaging.
It two is, gear direct-coupled with it and is that this gear is fixing vertically with a support (not shown) along axially can sliding mutually in export pipeline 204 and the downstream driving gear set 307.
As a kind of embodiment, can fix culture chamber 107 with stationary installation (not shown) such as support, thereby being cultivated inlet ductwork 202 and export pipeline 204 and treating between them, culture chamber 107 keeps static when vascular tissue 108 rotates.
As another kind of embodiment, culture chamber 107 does not link to each other with any stationary installation, thus make culture chamber 107 inlet ductwork 202 and export pipeline 204 and treating between them cultivate vascular tissue 108 when rotating also along with rotation.
Embodiment shown in Figure 3 further comprise one be used to gather, handle, the part of demonstration and/or record data.As shown in Figure 3, this is used to gather, handle, one of the part of demonstration and/or the record data concrete but embodiment of indefiniteness comprises: be located at the pressure transmitter 301 of culture chamber ingress, be used for detecting the pressure of the ingress of priming line culture chamber 107 in the blood vessel; Be located at the pressure transmitter 308 in culture chamber exit, be used for detecting the pressure in the exit of the dynamic culture chamber 107 of priming line in the blood vessel; Be located at the displacement sensor 311 on the stretching motor, be used to detect the amount of tension of vascular tissue 108; Concentrator 313, its receiving sensor 308 and 311 output; Small signal amplifier 314, it is from the output of concentrator 313 receiving sensors 307 and 309 and amplify; Driving mechanism 315; Treater 316, it can be a PC or industrial computer; Indicating meter 317.
It should be understood that above-mentioned gear unit 304,307, just realize the corresponding example that rotates the rotation transmission device that transmits; Also can replace gear unit 304 and/or 307, these other transmission mechanism such as chain gearing, belt transmission, transmission rod or the like with other transmission mechanism.Such distortion belongs to scope of the present invention.
Fig. 4 has shown a further concrete non-limiting embodiment of the present invention, and it compares the part of the outer filling of the vascular tissue 108 that has comprised that further realization is cultivated with embodiment shown in Figure 2.
As shown in Figure 4, the part of realization blood vessel outer filling comprises: outer filling loop liquid storage bottle 401; Outer filling liquid driving device 402, it links to each other through liquid line with liquid storage bottle 401; Outer filling loop culture chamber inlet ductwork 404, it passes the sealing plug 203 of upstream and leads to culture chamber 107 inside, is used for the nutrient solution from outer filling loop liquid storage bottle 401 is injected in the culture chamber 107; And, outer filling loop culture chamber export pipeline 407, the sealing plug 203 that it passes the downstream is used for nutrient solution is drawn from culture chamber 107.
As a kind of optional distortion, in embodiment shown in Figure 4, be provided with optional outer filling loop culture chamber inlet pressure sensor 403 and outer filling loop culture chamber outlet pressure sensor 408, be respectively applied for the liquid pressure in the outer filling loop of detecting culture chamber import and exit.Transmitter 403 and 408 output are sent to concentrator 313, with by treater 316 with indicating meter 317 is handled, write down and/or demonstration etc.
Embodiment shown in Figure 4 on the basis of embodiment shown in Figure 3, has been realized the nutrient solution perfusion in the vascular tissue outside in the culture chamber further.
By embodiment shown in Figure 4, can realize simultaneously or individually: the perfusion of the perfusion of blood vessel inner looping, blood vessel external loop, the stretching of vascular tissue, the pulsation (pulsating flow that intravascular pressure is strong, be the pulsation of the pressure difference of the inside and outside liquid of blood vessel), and any combination of these function/effects.
Should be appreciated that, because the pulsating flow in the pipe is corresponding to the fluctuation of the pressure difference of liquid in perfusion loop in the pipe and the pipe outer filling loop.So,, also can be arranged on pulsation source on the pipe outer filling loop as a concrete but infinite embodiment of the present invention; Perhaps, a further concrete but infinite embodiment of the present invention can pour into the pulsation source that is provided with simultaneously on the loop separately in blood vessel outer filling loop and blood vessel.These distortion all belong to scope of the present invention.
Perfusion stretches in embodiment 1 pulsating flow
1. according to pouring into the loop in the connection blood vessel shown in Figure 2, the perfusion fluid drive unit is a pulsation source in its medium vessels;
2. reactor is carried out disinfection, conditions for sterilization is: 130 ℃, and 3 normal atmosphere, 1 hour time;
3. engineering blood vessel that will be to be cultivated under sterile state is installed in vascular tissue's culture chamber medium vessels on the upstream and downstream pipeline in perfusion loop, engineering blood vessel internal diameter vessel diameter 6mm wherein, and length is 20cm, PLGA;
4. according to connection shown in Figure 2 vascular tissue stretching device, wherein vascular tissue's stretching motor is selected Hayden's 57000 serial linear stepping motors for use;
5. require the preparation substratum according to cultivating, aseptic culture medium is injected pour into liquid storage bottle in the blood vessel;
6. open the power supply preheating of each equipment;
7. the perfusion ripple frequency is 70 times/minute in the setting blood vessel, and the motor gain is 1-5%, sets starting position; Setting the interior irrigation flow of blood vessel is 0-1.6ml/s, and intake pressure is 100-140mmHg, and top hole pressure is 75-115mmHg;
8. setting the periodicity tensile stress that vascular tissue is subjected to is 10N, and stretching frequency is 60 times/min;
9. operation reactor;
10. regulate dragulator and conformability setter, pressure, the flow waveform in controlling flow intravascular tissue culture chamber, the arterial pulse wave waveform of analogy under physiological status;
Perfusion stretching internal rotation in embodiment 2 pulsating flows
1. according to pouring into the loop in the connection blood vessel shown in Figure 3, the perfusion fluid drive unit is a pulsation source in its medium vessels;
2. reactor is carried out disinfection, conditions for sterilization is: 130 ℃, and 3 normal atmosphere, 1 hour time;
3. engineering blood vessel that will be to be cultivated under sterile state is installed on the liquid dispenser of vascular tissue's culture chamber upstream and downstream, engineering blood vessel internal diameter vessel diameter 4mm wherein, and length is 10cm, PLGA;
4. according to connection shown in Figure 3 vascular tissue swivel arrangement, wherein vascular tissue's rotating machine is selected Hayden's 57000 serial stepper-motors for use;
5. the pressure transmitter of importing and exporting according to perfusion medium vessels tissue culture chamber, loop in the connection blood vessel shown in Figure 3, and signal supervisory instrument;
6. according to connection shown in Figure 3 vascular tissue stretching device, wherein vascular tissue's stretching motor is selected Hayden's 57000 serial linear stepping motors for use;
7. according to connection vascular tissue's tensile tension-compression sensor shown in Figure 3 and displacement sensor;
8. require the preparation substratum according to cultivating, aseptic culture medium is injected pour into liquid storage bottle in the blood vessel;
9. open the power supply preheating of each equipment;
10. the perfusion ripple frequency is 70 times/minute in the setting blood vessel, and the motor gain is 1-5%, sets starting position; Setting the interior irrigation flow of blood vessel is 0-1.6ml/s, and intake pressure is 100-140mmHg, and top hole pressure is 75-115mmHg;
11. set turning to and rotating speed of vascular tissue's rotating machine: be rotated counterclockwise 10rpm;
12. the periodicity tensile stress that setting vascular tissue is subjected to is 10N, stretching frequency is 60 times/min;
13. operation reactor;
14. regulate dragulator and conformability setter, pressure, the flow waveform in controlling flow intravascular tissue culture chamber, the arterial pulse wave waveform of analogy under physiological status;
The perfusion outer filling stretches in embodiment 3 pulsating flows
1. according to the inside and outside perfusion of connection blood vessel shown in Figure 4 loop, the perfusion fluid drive unit is a pulsation source in its medium vessels, and blood vessel outer filling liquid driving device is peristaltic pump (Cole-Parmer company, a Masterflex series);
2. reactor is carried out disinfection, conditions for sterilization is: 130 ℃, and 3 normal atmosphere, 1 hour time;
3. engineering blood vessel that will be to be cultivated under sterile state is installed on the liquid dispenser of vascular tissue's culture chamber upstream and downstream, engineering blood vessel internal diameter vessel diameter 6mm wherein, and length is 20cm, PLGA;
4. the pressure transmitter of importing and exporting according to medium vessels tissue culture chamber, the inside and outside perfusion of connection blood vessel shown in Figure 4 loop, and signal supervisory instrument;
5. according to connection shown in Figure 4 vascular tissue stretching device, wherein vascular tissue's stretching motor is selected Hayden's 57000 serial linear stepping motors for use;
6. according to connection vascular tissue's tensile tension-compression sensor shown in Figure 4 and displacement sensor;
7. require the preparation substratum according to cultivating, aseptic culture medium is injected perfusion liquid storage bottle and blood vessel outer filling liquid storage bottle in the blood vessel;
8. open the power supply preheating of each equipment;
10. the perfusion ripple frequency is 70 times/minute in the setting blood vessel, and the motor gain is 1-5%, sets starting position; Setting the interior irrigation flow of blood vessel is 0-1.6ml/s, and intake pressure is 100-140mmHg, and top hole pressure is 75-115mmHg; Blood vessel outer filling flow is 0-1.0ml/s, and intake pressure is 110-140mmHg, and top hole pressure is 85-110mmHg;
11. the periodicity tensile stress that setting vascular tissue is subjected to is 10N, stretching frequency is 60 times/min;
13. operation reactor;
14. regulate dragulator and conformability setter, pressure, the flow waveform in controlling flow intravascular tissue culture chamber, the arterial pulse wave waveform of analogy under physiological status.
Claims (6)
1. vascular tissue engineering reactor comprises:
By pouring into liquid storage bottle (101), pulsation source (102), the interior perfusion of blood vessel loop culture chamber inlet ductwork (202) in the continuous successively blood vessel of liquid line as perfusion fluid drive unit in the blood vessel;
Vascular tissue's culture chamber (107), an end of described culture chamber inlet ductwork (202) enter into vascular tissue's culture chamber (107) and with vascular tissue (108) to be cultivated thus an end be connected and be used to make the inside that flows into described vascular tissue (108) from the nutrient solution that pours into liquid storage bottle (101) in the described blood vessel;
Perfusion loop culture chamber export pipeline (204) in the blood vessel, the one end enter into described vascular tissue culture chamber (107) and with vascular tissue (108) to be cultivated thus the be connected nutrient solution of the inside that is used to derive described vascular tissue (108) of the other end
Wherein said pulsation source comprises:
A pulsation chamber (103), it is used for full of liquid;
Pass an elastic hose (104) in described pulsation chamber, this elastic hose has constituted and has poured into the part that liquid storage bottle (101) to the nutrient solution pipeline of described culture chamber inlet ductwork (202) passes described pulsation chamber in the described blood vessel;
Be arranged on the unidirectional non-return valve in upstream (111) at the upstream port place of elastic hose;
Be arranged on the unidirectional non-return valve in downstream (114) of the downstream port of described elastic hose;
Can act on the packed-piston (113) on the liquid in the described pulsation chamber;
Linear electric motors (112), it is reciprocating to be used to drive described packed-piston, thereby the liquid that is full of in the pulsation chamber (103) is produced squeezing action by described packed-piston, this squeezing action and then be delivered on the nutrient solution in the described elastic hose, thereby produce from pouring into the nutrient solution pulsating flow of liquid storage bottle (101) in the blood vessel to the inside of described vascular tissue (108)
It is characterized in that described vascular tissue engineering reactor further comprises:
Be arranged on one first dragulator (105) in described pulsation source (102) downstream, be used for regulating the perfusion pressure of nutrient solution of culture chamber (107) and waveform, the wave amplitude of nutrient solution perfusion pressure change;
Be arranged on one the first conformability setter (106) between described first dragulator (105) and the described culture chamber, be used for regulating the inertial flow of the nutrient solution of culture chamber;
Be arranged on one the second conformability setter (109) in described culture chamber downstream, be used for regulating the inertial flow of the nutrient solution of culture chamber;
Be arranged on one second dragulator (110) in described second conformability setter (109) downstream, be used for regulating the perfusion pressure of nutrient solution of described culture chamber and waveform, the wave amplitude of nutrient solution perfusion pressure change.
2. vascular tissue engineering reactor as claimed in claim 1 is characterized in that this reactor further comprises:
A tensile driving device (207), one of perfusion culture chamber export pipeline (204) is coupled in its stretch driving output and the interior perfusion culture chamber inlet ductwork (202) of described blood vessel and described blood vessel, thereby drive in the described blood vessel in the perfusion culture chamber inlet ductwork (202) and described blood vessel between the perfusion culture chamber export pipeline (204) axial doing relatively reciprocating motion, thereby realize being arranged on the reciprocal stretching of the vascular tissue (108) between the perfusion culture chamber inlet ductwork (202) and the interior perfusion culture chamber export pipeline (204) of described blood vessel in the described blood vessel along them.
3. vascular tissue engineering reactor as claimed in claim 2 is characterized in that this reactor further comprises:
Vascular tissue's rotational drive motor (310);
The upstream rotation transmission device (304) and the downstream rotation transmission device (307) that are coupled with the rotation axis of described drive-motor (310), wherein said upstream rotation transmission device (304) also is coupled with described culture chamber inlet ductwork (202), and described downstream rotation transmission device (307) also is coupled with described culture chamber export pipeline (204), thereby when described drive-motor drives described upstream and downstream rotation transmission device, described culture chamber inlet ductwork (202) and culture chamber export pipeline (204) also are driven and rotate, thereby the vascular tissue to be cultivated (108) that is arranged between described culture chamber inlet ductwork (202) and the described culture chamber export pipeline (204) is rotated.
4. vascular tissue engineering reactor as claimed in claim 3 is characterized in that this reactor further comprises:
An outer filling loop liquid storage bottle (401);
An outer filling liquid driving device (402), it links to each other by liquid line with described outer filling loop liquid storage bottle (401);
An outer filling loop culture chamber inlet ductwork (404), it links to each other with described outer filling liquid driving device (402) by liquid line, and it enters into described culture chamber (107) inside, thereby is used for handle from the space outside the vascular tissue (108) described in the nutrient solution injection culture chamber (107) of outer filling loop liquid storage bottle (401); And
An outer filling loop culture chamber export pipeline (407), its upstream extremity enter in the described culture chamber (107), and its downstream end extends to outside the described culture chamber (107), are used for the nutrient solution outside the described vascular tissue (108) in the described culture chamber is drawn.
5. vascular tissue engineering reactor as claimed in claim 4 is characterized in that this reactor further comprises:
An interior priming line upstream coupling (303) is used to realize being tightly connected between the pipeline that does not rotate of perfusion culture chamber inlet ductwork (202) and its upstream in the rotary described blood vessel;
An interior priming line downstream coupling (309), being tightly connected between the nutrient solution pipeline that does not rotate that is used to realize the interior perfusion culture chamber export pipeline (204) of rotating described blood vessel and be connected to perfusion liquid storage bottle (101) in the blood vessel;
A upstream nutritive medium divider (305), it is connected with the downstream end of perfusion culture chamber inlet ductwork (202) in the described blood vessel;
A downstream nutritive medium divider (306) that is connected with perfusion culture chamber export pipeline (204) upstream extremity in the described blood vessel;
Wherein many vascular tissues to be cultivated are set between described upstream nutritive medium divider (305) and the downstream nutritive medium divider (306), when described upstream nutritive medium divider (305) and downstream nutritive medium divider (306) have been realized these many vascular tissues in the perfusion and the rotation;
A upstream seal plug (203), its mode with rotatable sealing combines with described culture chamber, and perfusion culture chamber inlet ductwork (202) and described outer filling loop culture chamber inlet ductwork (404) are passed this upstream seal plug (203) and entered described culture chamber (107) in the mode that seals in the described blood vessel;
A downstream sealing plug (203), its mode with rotatable sealing combines with described culture chamber, and perfusion culture chamber export pipeline (204) and described outer filling loop culture chamber export pipeline (407) pass described downstream sealing plug (203) in the mode that seals and extend to outside the described culture chamber (107) in described culture chamber (107) in the described blood vessel;
Tension-compression sensor (302) is used for detection effect pulling force on the perfusion culture chamber inlet ductwork (202) in described blood vessel;
A displacement sensor (311) is used to detect the displacement that perfusion culture chamber export pipeline (204) is taken place in the blood vessel;
Be located at the pressure transmitter (301) of culture chamber ingress, be used for detecting the pressure of the ingress of priming line culture chamber (107) in the blood vessel;
Be located at the pressure transmitter (307) in culture chamber exit, be used for detecting the pressure in the exit of the dynamic culture chamber (107) of priming line in the blood vessel;
Outer filling loop culture chamber inlet pressure sensor (403) is used for detecting the liquid pressure in the outer filling loop of culture chamber ingress;
Outer filling loop culture chamber outlet pressure sensor (408) is used for detecting the liquid pressure in the outer filling loop in culture chamber exit;
Concentrator (313), it receives the output of each transmitter;
Small signal amplifier (314), it receives the output of each transmitter and amplifies from concentrator (313);
Driving mechanism (315);
Treater (316); And
Indicating meter (317).
6. vascular tissue engineering reactor as claimed in claim 2, wherein said tensile driving device (207) are linear electric motors (207).
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200810102145 CN101372663B (en) | 2008-03-18 | 2008-03-18 | Vascular tissue engineering reactor having vas stretch and pulsating flow pouring functions |
| US12/344,586 US20090181448A1 (en) | 2007-12-28 | 2008-12-28 | Perfusion type vascular tissue bioreactor with rotary and stretching functions |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200810102145 CN101372663B (en) | 2008-03-18 | 2008-03-18 | Vascular tissue engineering reactor having vas stretch and pulsating flow pouring functions |
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| CN101372663B true CN101372663B (en) | 2011-07-27 |
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| CN102296029B (en) * | 2010-06-28 | 2013-01-30 | 裴国献 | Perfusion bioreactor system |
| CN101880629A (en) * | 2010-07-22 | 2010-11-10 | 康阳扬 | Rotary tissue stress culture system and method |
| CN104342370B (en) * | 2014-05-28 | 2016-08-10 | 中国科学院力学研究所 | The biomechanical system cultivated for cell three-dimensional perfusion Compression and Expansion |
| CN106137456B (en) * | 2015-03-31 | 2018-09-14 | 四川蓝光英诺生物科技股份有限公司 | A kind of rotating device and its application method for biometric print |
| CN106591121B (en) * | 2016-11-30 | 2019-04-05 | 广州博敏科技有限公司 | Rotating and culturing room and rotary pulse culture systems |
| CN106754356B (en) * | 2016-11-30 | 2019-07-23 | 广州迈普再生医学科技股份有限公司 | Three-dimensional perfused culture system and the histoorgan of 3D printing |
| CN111226911B (en) * | 2020-03-12 | 2023-12-12 | 美茵（北京）医疗器械研发有限公司 | Bridge vascular tissue perfusion system and perfusion method |
| CN115491305B (en) * | 2022-11-17 | 2023-03-10 | 季华实验室 | Tissue engineering blood vessel culture ware, culture apparatus and system |
| CN115786116A (en) * | 2023-01-09 | 2023-03-14 | 季华实验室 | Culture apparatus and reactor for tissue engineering culture |
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