CN101012433A - Groove shape porous plate animal cell hollow fiber reactor and use thereof - Google Patents
Groove shape porous plate animal cell hollow fiber reactor and use thereof Download PDFInfo
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- CN101012433A CN101012433A CN 200610053989 CN200610053989A CN101012433A CN 101012433 A CN101012433 A CN 101012433A CN 200610053989 CN200610053989 CN 200610053989 CN 200610053989 A CN200610053989 A CN 200610053989A CN 101012433 A CN101012433 A CN 101012433A
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Abstract
The invention discloses a hollow fiber reactor of groove-shaped porous animal cell, which comprises the following parts: upper lid, porous board chassis and hollow fiber yarn, wherein 6-24 semi-circular flutes are carved on the porous board chassis with 1-20 hollow fiber yarn in each flute; the animal cell gel is buried in the hollow fiber yarn, which transmits oxygen and mass for cell. The invention combines microminiaturized superiority of porous board with three-dimensional bionic culturing superiority of artificial liver reactor, which keeps the biological activity of animal cell.
Description
Technical field
The present invention relates to a kind of extracorporeal culturing method of zooblast, especially, relate to a kind of groove shape porous plate animal cell hollow fiber reactor.
Background technology
Liver is the vitals in the human body, has functions such as synthetic, metabolism and detoxifcation.The liver that only accounts for human body 2.6% often is compared to comprehensive biochemistry factory in the body, has multiple as metabolism functions such as sugar, lipid, protein, Metabolism Vitamins and Hormones.Often Toxic, medicine etc. enter in the body in the whole vital process of organism, self also produce interior toxicant in the body simultaneously in metabolic process.These material major parts are carried out the metabolism transformation by liver and have been increased polarity or water-soluble, help excreting with urine or bile, also change its toxicity or pharmacological action simultaneously.This poisonous substance or medicine metabolism transition process in vivo is called as biotransformation.Equally, medicine changes through physico-chemical property takes place behind the liver metabolism, influences its pharmacological action.In addition, medicine and drug interaction cause the rapid quickening of inducing of drug metabolism or are suppressed, and have reduced or improved the active drug concentration of purpose medicine on site of action, lose drug effect or enrichment causes visceral organ injury.So the drug metabolism study of liver is one of committed step of clinical medicine screening in advance.
Along with the development with rapid changepl. never-ending changes and improvements of chemical industry and biosynthesis ability, a large amount of new drugs await screening and exploitation.Coming simulated liver biological function in vivo with former generation animal liver cell model of vitro culture is one of present important research direction.And the main place of the liver cell that accounts for liver 90% (weight) to be liver carry out drug metabolism and reflection use in medicament-induced hepatotoxicity is the living things system of ideal drug metabolism study.At present, the foreign study that liver cell is used for drug metabolism mainly contains following three characteristics: the first, because the healthy human body liver cell is difficult to obtain, adopt the free liver cell that enzymolysis obtains from animal livers usually; The second, free liver cell all adopts the culture dish monolayer culture or the two-layer gel intermediary interlayer that scribble collagen to cultivate, and makes survival time can reach a couple of days to a few weeks longer; The 3rd, for improving drug screening efficient, mostly adopt the porous culture dish, it is microminiaturized that scale tends to gradually.Can avoid zooperal drawback,, individual difference low as efficient cause greatly result error excessive, be unfavorable for shortcomings such as protection of animal, can't eliminate species variation.
At present, the cell in vitro model that is used for drug research mainly contains orifice plate cultivation and plate cultivation etc., though the mode of this kind two dimension is simple to operate, but keep the cytoactive time short, cell function is easily lost, the good 26S Proteasome Structure and Function of analogue body inner cell, these defectives are restricted its application.Existing liver cell vitro culture mode mostly adopts the monolayer culture of two dimension, liver cell need be on the surface of culture vessel could adherent growth, cell is island, and albumen urea and various drug metabolism function often significantly descend in a couple of days even completely lose, and survival time is usually about a week.Therefore liver cell has very big-difference in cell phenotype, function and the body of monolayer culture, also can't replace the interior liver cell of body to finish liver function.Realize liver cell critical function in vivo in order to study better, developed at present and some dimensional culture technology, as by collagen gel embedding or the poly-spheroid of formation liver cell, the mode that liver cell is adopted in the vitro culture process and the body physiological state is more approaching is cultivated.Wherein the poly-spheroid cultivation of liver cell is to study cultural method of greatest concern at present.And the dimensional culture mode, as tubular fibre bioartificial liver reactor, though can the long period keep cell function, the simulated liver environment, but complex structure needs the circulation of multichannel oxygen supply and substratum, and is bulky, cost is also quite high, obviously is not suitable for the drug metabolism study and the high-throughout drug screening that need miniaturization.
Simultaneously, laboratory study cell culture condition and production products of cellular metabolism need a kind of miniaturization, the device that is fit to carry out condition experiment, optimization, screening.And the large-scale hollow fiber reactor that industrial production is used obviously can't meet this requirement.If can find training method a kind of not only simple to operate but also that amplify easily, certain meaning is arranged for the early-stage Study of zooblast suitability for industrialized production.
Summary of the invention
The objective of the invention is to deficiency at existing drug research model, a kind of groove shape porous plate animal cell hollow fiber reactor is provided, required structure of general reactor and operation have been simplified greatly, by collagen gel animal is embedded in the hollow fibre filament, collagen has been simulated the reticular tissue in the intracorporeal organ, the porous hollow fibre filament has then been simulated blood vessel in the body, nutrition and oxygen are from being diffused into the hollow surface with the sufficient substratum of air, seeing through behind the macaroni yarn wall at the gel internal diffusion to cell surface the then anti-phase substratum that diffuses to of metabolism h substance.This culture systems reaches the bionics effect in the mode of dimensional culture, and can long term maintenance zooblast function.
The technical scheme that the present invention adopts for achieving the above object is: a kind of groove shape porous plate animal cell hollow fiber reactor, comprise son with cover, porous plate base and hollow fibre filament, be carved with 6～24 semi-circular recesses on the described porous plate base, each groove contains 1～20 hollow fibre filament, the zooblast gel embedding is incubated in the described hollow fibre filament.
The present invention also aims to provide the purposes of groove shape porous plate animal cell hollow fiber reactor.
The technical scheme that the present invention adopts for achieving the above object is: it can keep the biological activity of zooblast, realizes the following purposes of zooblast:
(1) is the purposes of the animal liver cell external model of the research of drug metabolism and pharmacological toxicology;
(2) be used for the purposes of the laboratory study that cell culture condition and product produce.
The useful effect that the present invention has is: can carry out long-term dimensional culture to zooblast, simplify the operation steps of zooblast dimensional culture greatly, make things convenient for the application of animal cultivation in research and drug screening.The disclosed technology of present technique can keep the biological activity of zooblast, realizes the multiple use of zooblast.Specifically, the one, as the animal liver cell external model of the research of drug metabolism and pharmacological toxicology, the 2nd, be used for the laboratory study that cell culture condition and product are produced.And can be used as the carrier of animal cell culture condition research, for suitability for industrialized production lays the foundation.With the liver cell is example; culture technique provided by the invention can make liver cell carry out dimensional culture; be similar to hepatocellular weave construction in the liver, can reflect better medicine to the possible toxicity of liver or provide protection and medicine in the intravital metabolic conversion reaction of liver.
Description of drawings
Fig. 1 is the structural representation of the flute profile orifice plate hollow fiber reactor of 24 grooves.
Fig. 2 be among the embodiment 1 24 hole monolayer adherences cultivate and 24 hole-and-slot orifice plate tubular fibres cultivation liver cell to the pharmaceutically-active response in vazadrine.Wherein (A) is the cell motility rate; (B) be the urea synthesis level; (C) be the synthetic level of albumin; (D) be born of the same parents' glutathion inside level.
Fig. 3 be among the embodiment 2 24 hole monolayer adherences cultivate and 12 hole-and-slot orifice plate tubular fibres cultivation liver cell to the pharmaceutically-active response of Ta Kening and to the response of Potenlini hepatoprotective effect.(A) cell motility rate wherein; (B) be to be born of the same parents' glutathion inside level in the born of the same parents.
Fig. 4 is that the 6 hole-and-slot orifice plate tubular fibres of embodiment 3 are cultivated the curve that liver cell carries out drug metabolism, wherein (A) is that monolayer adherence liver cell (■-) and gel embedding human liver cell (◆-) metabolism phenacetin generates the bio-transformation ability of acetaminophen, and this reaction has characterized the enzymes metabolism ability of CYP1A2; (B) monolayer adherence liver cell (■-) and gel embedding liver cell (◆-) metabolism generates the bio-transformation ability of 4-nitro-pyrocatechol, and this reaction has characterized the enzymes metabolism ability of CYP2E1.
Fig. 5 is that the 24 hole monolayer adherences of embodiment 4 are cultivated and flute profile orifice plate tubular fibre reaction cultivation liver cell carries out the indirect measurement of Rheumatrex bile excretion ability.The hepatocellular cell motility rate of (A) monolayer adherence wherein; (B) be the hepatocellular urea synthesis level of gel embedding; (C) be the synthetic level of the hepatocellular albumin of monolayer adherence; (D) be the synthetic level of the hepatocellular albumin of gel embedding cell.
Embodiment
Groove shape porous plate animal cell hollow fiber reactor of the present invention comprises that son with cover, porous plate base, each groove of being carved with 6～24 semi-circular recesses down contain the hollow fibre filament more than 1; Every macaroni yarn inner chamber embedding (collagen gel is fixed) zooblast.
The orifice plate material is transparent low toxin polystyrene material material.The outstanding numeral in bottom clearly marks the position of groove, and the design of gas grid makes things convenient for gaseous interchange and guarantees that performance of ventilating is superior, and configuration design is with common commercially available Tissue Culture Plate, can conveniently stack, in addition, this orifice plate can be through Gamma gamma ray sterilization, non-returnable container.
The material of hollow fibre filament is polypropylene, polysulfones, polyacrylonitrile or the polyethylene of its molecular weight cut-off at 100KDa～1000KDa.
Cell cultures is that cell is in collagen gel is embedded in hollow fibre filament.Results are obtained former generation zooblast and the conventional animal cell strain by 10
6-10
7Cell/ml density was inoculated in 1: 3, in the 4 times of enrichment mediums and mouse tail collagen solution mixed solution of v: v, inject hollow fibre filament, place for 20-37 ℃ and solidified in 10-15 minute, hollow fibre filament is cut short to 6-8cm, put the celliferous macaroni yarn of 1-20 root in each groove of groove shape porous plate, add the substratum that 1-5 milliliter incubation is crossed in every groove, so just form described flute profile orifice plate hollow fiber reactor.
Each groove contains the cavity volume that is embedded with cell for 0.1ml-2ml, and its volume size depends on the radical of hollow fibre filament.Each orifice plate can be opened 6 to 24 groove number, and it is fixed that concrete groove number then comes as required.
The invention will be further described below in conjunction with drawings and Examples.
As shown in Figure 1, the present invention includes: the Tissue Culture Plate of band-slot cylindrical void comprises that the porous plate base that descends to be carved with many semi-circular recesses, last son with cover, each groove contain the hollow fibre filament more than 1; Every macaroni yarn inner chamber embedding (collagen gel is fixed) zooblast.The flute profile Tissue Culture Plate is similar to the conventional individual layer that is used for and pastes 12 holes or the 24 porocyte culture plates that an ancient piece of jade, round, flat and with a hole in its centre is cultivated, just the shape and the cell cultures mode difference in hole.
The comparison of specific embodiment 1:(on the drug toxicity of vazadrine)
The results motility rate is higher than 90% rat hepatocytes by 10
6Cells/ml density was inoculated in 4 times of enrichment mediums and mouse tail collagen solution mixed solution (1: 3; V: v), inject 3,37 ℃ of placements of hollow fibre filament and made it to solidify in 10 minutes.Hollow fibre filament 3 is cut short, and 6.5cm * 12 piece in the groove of per 3 24 groove flute profile orifice plates of packing into, add 3ml and contain 5% foetal calf serum Williams ' E substratum, put into 37 ℃, 5%CO
2Incubator leaves standstill cultivation.
Will be with batch rat hepatocytes by 0.8 * 10
6Cells/ml inserts 3ml and contains in the 24 porocyte culture plates that are covered with mouse tail collagen of 5% foetal calf serum Williams ' E substratum.Culture condition is same as described above.
Treat in the 24 porocyte culture plates behind the cell attachment (12-18h), in hollow fiber reactor and plate, add respectively and contain medicine to be measured vazadrine substratum and do not contain medicine substratum (as blank).Thereafter the substratum that every 60h more renews.Each repeats three groups, measures liver cell motility rate and liver function index urea and albumin.The result as shown in Figure 2.
As seen from Figure 2, the gel embedding liver cell is more responsive than pasting ancient piece of jade, round, flat and with a hole in its centre cell to the reaction of liver toxicity medicine vazadrine, has illustrated that the liver cell of dimensional culture more is applicable to drug toxicity research than monolayer adherence liver cell.
General porous cell culture plate often is used as the carrier of cells in vitro, is usually used in the monolayer culture of two dimension.Therefore, experiment finds that flute profile orifice plate tubular fibre Tissue Culture Plate is more superior than conventional porous cell culture plate, and the difference of the present invention and porous plate also can be described.
Specific embodiment 2:(is used for the evaluation of hepatic)
The results motility rate is higher than 90% rat hepatocytes by 10
6Cells/ml density was inoculated in 4 times of enrichment mediums and mouse tail collagen solution mixed solution (1: 3; V: v), inject 3,37 ℃ of placements of hollow fibre filament and made it to solidify in 10 minutes.Hollow fibre filament 3 is cut short, and 6.2cm * 12 piece in the groove of per 3 12 groove flute profile orifice plates of packing into, add 3ml and contain 5% foetal calf serum Williams ' E substratum, put into 37 ℃, 5%CO
2Incubator leaves standstill cultivation.
After cultivating 12-18h, each group changes to respectively that to contain drug level be the Potenlini of 0.25mM Ta Kening, 0.25mM Ta Kening+0.5g/l and the substratum (as blank) that does not contain medicine.Observation of cell form behind the 48h, the cell motility rate and the gsh of the Potenlini of discovery 0.25mM Ta Kening+0.5g/l are all higher, approach blank, have compared significant improvement and raising with the Ta Kening group.
Specific embodiment 3:(is used for drug metabolism study)
The results motility rate is higher than 90% human liver cell by 10
6Cells/ml density was inoculated in 4 times of enrichment mediums and mouse tail collagen solution mixed solution (1: 3; V: v), inject 3,37 ℃ of placements of hollow fibre filament and made it to solidify in 10 minutes.Hollow fibre filament 3 is cut short, and 6.5cm * 12 piece in the groove of per 3 24 hole-and-slot orifice plates of packing into, add 3ml and contain 5% foetal calf serum Williams ' E substratum, put into 37 ℃, 5%CO
2Incubator leaves standstill cultivation.
Will be with batch rat hepatocytes by 0.8 * 10
6Cells/ml inserts the culture hole that 2ml contains the 24 porocyte culture plates that are covered with mouse tail collagen of 5% foetal calf serum Williams ' E substratum.Culture condition is same as described above.
After cultivating 60h, each group adds drug metabolism substrate (the Phenacetin solution of 40uM and 4-nitro-pyrocatechol, 4-NC), be respectively the specific substrate of CYP1A2 and CYP2E1), drug metabolism through 3h, the HPLC method is measured meta-bolites (Phenacetin and 4-nitro-pyrocatechol, 4-NC) content of each substrate.The result as shown in Figure 4.As seen from the figure, human liver cell is higher than the plate culturing cell in the ability of hollow fiber reactor intracellular metabolite Phenacetin and 4-nitro-pyrocatechol, illustrates that cytochrome C YP1A2 and CYP2E1 can keep enzymic activity better than plate monolayer culture.And the liver cell of common vitro culture very fast disappearance relative medicine metabolic enzyme in 12 hours is lived.Therefore the tubular fibre gel embedding is cultivated than the cultivation of Tissue Culture Plate monolayer adherence and more is applicable to drug metabolism study.
Specific embodiment 4:(is used to observe medicine bile excretion ability)
The liver cell that 24 porocyte culture plate monolayer adherences are cultivated and cultivated in 24 groove flute profile orifice plate hollow fiber reactors carries out drug absorption and excretory curve; Adopt fluorescein (fluorescein diacetate) secretion Experimental Characterization monolayer adherence liver cell or the hepatocellular choleresis function of gel embedding.Monolayer adherence liver cell or gel embedding liver cell in containing the Willam E substratum of 0.125mg/ml fluorescein, behind the incubation 30min, are observed to be under fluorescent microscope and crawl in the 37C incubator, and observing wavelength is 495nm and 520nm.From fluorescence photo (figure slightly) as can be known, monolayer adherence is cultivated hepatocellular fluorescence bile duct passage and not obvious, and that gel is cultivated hepatocellular fluorescence biliary tract is very clear.In addition, adopt the drug effect of methotrexate to observe the bile duct discharge capacity, behind the liver cell culture 4h that monolayer adherence is cultivated, respectively substratum is changed into and do not add any medicine, contain the 1mmol/L Rheumatrex and contain the substratum of 5mmol/L Rheumatrex, change substratum behind the 48h again.To the monolayer adherence liver cell, cultivation 24 and 72h post analysis cell motility rate, urea and albumin output; Gel is cultivated liver cell, cultivate 120 hours post analysis liver function indexs.Result such as Fig. 4.Obviously find out from figure, the monolayer adherence liver cell is very responsive to the drug effect of methotrexate, and the gel embedding cell does not then have significant toxic reaction in 72h, reaction is to a certain degree only just arranged under the effect of 5 day time.In the rat body, the methotrexate of about 70-90% is by bile excretion.Because the hepatocellular little gall-bladder structure of monolayer adherence is complete like that and abundant not as the gel embedding liver cell of three-dimensional tissueization, the hepatocellular little gall-bladder discharge capacity of monolayer adherence is not as the gel embedding liver cell.Therefore, Rheumatrex is just easily in monolayer adherence liver cell born of the same parents, because the cytotoxicity of itself causes the individual layer liver cell more to be sensitive to the toxicity of Rheumatrex than gel embedding liver cell.
The groove shape porous plate animal cell hollow fiber reactor that the present invention proposes, be described by preferred embodiment, person skilled obviously can be changed the present invention in not breaking away from content of the present invention, spirit and scope or suitably be changed with combination and realize the technology of the present invention.Special needs to be pointed out is, the replacement that all are similar and change apparent to one skilled in the artly, they all can be regarded as being included in spirit of the present invention, scope and the content.
Claims (6)
1. groove shape porous plate animal cell hollow fiber reactor is characterized in that: comprise son with cover, porous plate base and hollow fibre filament, be carved with 6～24 semi-circular recesses on the described porous plate base, each groove contains 1～20 hollow fibre filament.The zooblast gel embedding is incubated in the described hollow fibre filament.
2. groove shape porous plate animal cell hollow fiber reactor according to claim 1 is characterized in that, the material of described porous plate base is transparent low toxin polystyrene material.
3. groove shape porous plate animal cell hollow fiber reactor according to claim 1 is characterized in that, the material of described hollow fibre filament is polypropylene, polysulfones, polyacrylonitrile or the polyethylene of its molecular weight cut-off at 100KDa～1000KDa.
4. groove shape porous plate animal cell hollow fiber reactor according to claim 1 is characterized in that, it is that cell is in collagen gel is embedded in hollow fibre filament that described gel embedding is cultivated; 4 times of enrichment mediums and mouse tail collagen are prepared mixing solutions in 1: 3 ratio, again with zooblast by 10
6～10
7Cell/ml density is inoculated in this mixing solutions, inject hollow fibre filament, place for 20-37 ℃ and solidified in 10～15 minutes, hollow fibre filament is cut short to 6～8cm, put 1～20 celliferous macaroni yarn in each groove, add the substratum that 1～5 milliliter of incubation is crossed in each groove, so just form described flute profile orifice plate hollow fiber reactor.
5. groove shape porous plate animal cell hollow fiber reactor according to claim 1 is characterized in that, each contains the cavity volume that is embedded with cell of 0.1ml～2ml described groove, and each orifice plate can be opened 6～24 groove number.
6. the purposes of a groove shape porous plate animal cell hollow fiber reactor, this reactor comprises son with cover, porous plate base and hollow fibre filament, is carved with 6～24 semi-circular recesses on the described porous plate base, each groove contains 1～20 hollow fibre filament; The zooblast gel embedding is incubated in the described hollow fibre filament; It is characterized in that it can keep the biological activity of zooblast, realize the following purposes of zooblast:
(1) as the purposes of the animal liver cell external model of the research of drug metabolism and pharmacological toxicology.
(2) be used for the purposes of the laboratory study that cell culture condition and product produce.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102676369A (en) * | 2011-12-19 | 2012-09-19 | 河南科技大学 | Evaluation model for zinc biological effectiveness in foods and establishment method thereof |
| CN104619830A (en) * | 2012-09-06 | 2015-05-13 | 普拉里斯坦有限公司 | Devices and methods for culture of cells |
| CN105733944A (en) * | 2016-05-04 | 2016-07-06 | 浙江大学 | Construction method for six-pore plate hepatic cell hollow fiber reactor |
| WO2018192152A1 (en) * | 2017-04-19 | 2018-10-25 | 中国食品药品检定研究院 | Preparation and application of model for use in detecting in vitro endothelialization of vascular stent material |
| CN111704998A (en) * | 2020-07-14 | 2020-09-25 | 兰州大学第一医院 | Vertical plate constant-flow type biological artificial liver reactor |
-
2006
- 2006-10-27 CN CN 200610053989 patent/CN100540647C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102676369A (en) * | 2011-12-19 | 2012-09-19 | 河南科技大学 | Evaluation model for zinc biological effectiveness in foods and establishment method thereof |
| CN102676369B (en) * | 2011-12-19 | 2013-12-25 | 河南科技大学 | Evaluation model for zinc biological effectiveness in foods and establishment method thereof |
| CN104619830A (en) * | 2012-09-06 | 2015-05-13 | 普拉里斯坦有限公司 | Devices and methods for culture of cells |
| CN105385596A (en) * | 2012-09-06 | 2016-03-09 | 普拉里斯坦有限公司 | Devices and methods for culture of cells |
| CN105733944A (en) * | 2016-05-04 | 2016-07-06 | 浙江大学 | Construction method for six-pore plate hepatic cell hollow fiber reactor |
| WO2018192152A1 (en) * | 2017-04-19 | 2018-10-25 | 中国食品药品检定研究院 | Preparation and application of model for use in detecting in vitro endothelialization of vascular stent material |
| CN111704998A (en) * | 2020-07-14 | 2020-09-25 | 兰州大学第一医院 | Vertical plate constant-flow type biological artificial liver reactor |
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