CN101273119A - Novel enhanced processes for drug testing including neoplasmic tissue slices and products thereby - Google Patents
Novel enhanced processes for drug testing including neoplasmic tissue slices and products thereby Download PDFInfo
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Abstract
A novel method for testing neoplasmic tissue in a testing system is more effective than conventional cell culture systems and functions by treating the neoplasmic tissue slice system's samples with at least one compound and observing the effect on the neoplasmic tissue slices resident therein, or cells, tissue samples or other derivatives from the testing process, among other things.
Description
Technical field
The present invention relates to the system that is used to detect that uses together with biological tissue section, wherein biological tissue section comprises and derives from any major organs, tract, utilizes cloned tissue that somatocyte shifts or based on those biological tissue sections of the scheme (comprising Cord blood, any type of true tumor) of any other stem cell.This instant detector can be used as the method that individualized therapeutic treatment is provided and is used for estimating, surveys and detects drug candidate, medicine and drug metabolite.At last, this instant detector can be used to disease such as the carcinogenesis in the research organization, and wherein this tissue is selected based on phenotype analytical or any other protein science, genomics or metabolism group analytical procedure (comprising the nanosystems biological means).
Background technology
Determine that present mode has two main drawbacks for preceding the detection with the listing back of listing.For instance,
Failure make the following fact very clear: need extensive work to screen to be used for the material standed for of specific disease state, with make clear whether have that the part crowd has a untoward reaction may.Utilize present obtainable genome and proteomic analysis methods, can stand before this potential harmful and morbific toxic chemical examination high-risk patient and some type patients' tissue.
Equally, this operational method of the cost impact of increase (calculus) and emphasize and given prominence to needs to instruction of the present invention.This can become fully aware of after looking back the verified historical numeral in this area.
According to the research of Tufts Center for the Study of Drug Development, in calendar year 2001, the average cost of developing new drug thing is above 800,000,000 dollars.Among this, each company average spends about 1,600 ten thousand dollars and is used for preclinical study.Therefore, the reduction of detection time and expense is key factors for the existence of most of pharmaceuticals in the drug development.In addition, owing to have of the competition of above company an of family usually at same pharmaceutical field, so any competitive advantage is welcome.The major portion of drug development expense produces in the FDA ratification process.Yet most of this expense can not be to manage with clinical preceding expense in a like fashion.In order to solve expense before sharp increase clinical, the inside and outside detect and choose possible new drug candidate more efficient, can undertake and timely method industrial be very important.
In a kind of novel drugs of exploitation, toxicity is an important consideration aspect always.Because the hepatic metabolism most drug is so liver injury receives very big concern.Equally, how to react for foreign matter also be extremely important other organs and system and they.Therefore, utilize in the conventional bulk of animalcule and cell culture technology, vitro detection is widely used for assess liver function in drug development.Yet these traditional detection have specific shortcoming, as the difference of individuality, use the expensive of a large amount of animals, and the forfeiture of the natural characteristic of liver in situ.Like this equally for other organ.Along with how we reply the increase of the understanding of various prodrugs, medicine, compound and system to these other organs and Mammals, it is outstanding more and significantly that the relative importance of content of the present invention becomes.
In order to overcome these shortcomings, used cell culture system.Yet, utilize these models, connectivity between the cell interacts and can not keep the time span expected.In case the forfeiture of the connectivity between the cell, then detection scheme will soon be failed, because it is no longer at organ, system or the reaction of body level.
Bioartificial organ devices is in the exploitation at present.It is believed that the only available biological substrate of organ dysfunction (substrate), that is, for example liver slice or full liver sample (it requires the availability from the hepatic tissue in xenogenesis or tumour source) substitute.Nearest work has been held in the device at mixing (combination) type rami hepatici machinery and biological supporting system has been combined.The mechanical component of these hybrid devices had both played the effect of removing toxin, formed patients serum and this rami hepatici again and held barrier (blocking layer) between the biologic component of device.The biologic components of these mixed type supportive devices can constitute by liver slice, granulated liver or from the liver cell of rudimentary tumour cell or porcine hepatocyte.These biologic component are contained in and often are called the indoor of bio-reactor.Yet, for the functional still existing problems that remain on the individual cell lines of using in these devices.Most of devices use immortalized cell line (immortalized cell line).Have been found that As time goes on these cell forfeiture specific functions.
There are some groups developing bioartificial liver devices, for example, Circe
(Lexington, MA),
(La Jolla, CA), Excorp Medical (Oakdale, MN) and Algenix (Shoreview, MN).The liver cell that Circe Biomedical device can be survived with biocompatible membrane is integrated into extracorporeal bioartificial liver's subsystem.Vitagen ' s
(extracorporeal liver supplementary unit) artificial liver is a kind of two Room hollow fiber conduits, and it accommodates the tumour hepatic cell line (C3A) of cultivation.This pipe comprises the semi-permeable membranes with characterization molecular retention value.This film can carry out physical isolation with the tumor cell line of cultivation and patient's ultrafiltrated.Algenix provides a kind of system, and wherein outside rami hepatici is held system and used porcine hepatocyte.Individual porcine hepatocytes pass is by film, to handle neoplasmic blood cells.The device of Excorp Medical comprises a hollow-fibre membrane (having the 100kDa cutoff value) bio-reactor, and it separates the original porcine hepatocyte available from the no cause of disease pig of having a mind to raise that patient's blood and about 100 restrains.The cylinder of blood through filling with hollow polymer fiber and the suspension that contains tens porcine hepatocytes.Fiber serves as barrier and directly contacts patient's blood with the cell by-products that prevents albumen and pig cell, but allows contact necessary between these cells so that the toxin in the blood can be removed.
A lot of aspects of these devices provide the improvement on prior art, but they still have certain disadvantages.The effectiveness of these devices (it all uses individual hepatocyte) is restricted, and this is that it is the liver characteristic of state in vivo because of the interaction that lacks between the cell.Therefore, for the application in the drug development, have improved effectiveness, viability and functional bioartificial organ for example liver will be useful.This secular demand is solved by instruction of the present invention (for drug testing provides bio-artificial tissue slices).
Advance along with the technology of bioartificial organ system is lasting, improving one's methods of SCREENED COMPOUND also developed.In this application, disclosed the method that up-to-date improvement is applied to bioartificial organ system, particularly the scheme with exploitation is applied to tumor tissues.
Summary of the invention
Disclosed a kind of novel method that is used for tissue, cell culture and the tumor tissues of detection of biological artificial organs system itself, wherein by also observe influence (effect) with this bioartificial organ system of at least a compound treatment or cell culture to this bioartificial organ system or cell culture.Equally, those skilled in the art's easy to understand, what further disclose is a kind of business method, and being used to utilize apparatus and method of the present invention is the particular screen that the patient provides tissue and organ down to analyze auxiliary in incisxal edge genome, protein groups and metabolism group (metabonomic).
This paper has disclosed a kind of method that is used to provide situation (condition) in the mimic body, comprise and be provided for the bio-reactor that reappears intravital function of organization basically external, guarantee that this bio-reactor holds at least one aliquots containig of tissue sample, and make at least one aliquots containig can produce useful data.
Equally, disclosed a kind of method of the interior situation of analogue body basically that is used for, comprise that acquisition is used for the bio-reactor that duplicates intravital function of organization basically external, obtains a tissue sample, and utilizes at least one aliquots containig of this tissue sample to produce useful data.
Also further disclosed a kind of method of the interior situation of analogue body basically that is used for, comprise a kind of neoplasmic tissue sample is provided, this tissue sample is divided into tissue slice, introduce the part of this tissue slice as the bio-artificial tissue system, and by with at least a pharmaceutical admixtures (drug regimen) thus handle this tissue slice and use this bio-artificial tissue system to produce useful data.
Disclosed a kind of similar method, comprise the bio-artificial tissue system that obtains to contain tumor tissue section, thereby utilize this bio-artificial tissue system to produce useful data by handle tissue slice with at least a pharmaceutical admixtures, and toxicity or the histopathology of these data to define mitotic activity, compound relatively, select a kind of pharmaceutical admixtures based on the comparative result of data.
At last, disclosed a kind of business method that tumor tissues detects that is used for, comprised the system that is provided for holding tumor tissue section, this tumor tissues implantable bioartificial reactive group system based on bio-reactor, a kind of scheme of test on this tumor tissues, and collect the result.
Description of drawings
With reference to the description below in conjunction with accompanying drawing, the above-mentioned feature and the purpose of content of the present invention will be more obvious, and in the accompanying drawings, same numeral is represented similar elements, and wherein:
Fig. 1 is a kind of synoptic diagram of system of a kind of embodiment of bioartificial organ system;
Fig. 2 is the skeleton view of a kind of embodiment of a kind of tumor tissues of the content according to the present invention and bioartificial organ system;
Fig. 3 is the skeleton view of a kind of embodiment that is installed in the bio-reactor in a kind of tumor tissues and the bioartificial organ system of content according to the present invention;
Fig. 4 is a kind of skeleton view of embodiment of the system of Fig. 1 to Fig. 3;
Fig. 5 is the skeleton view of a kind of embodiment of system of the present invention, and it illustrates the placement of tumor tissue section;
Fig. 6 is a kind of exploded view of embodiment that comprises a kind of tissue slice equipment of tumor tissue section;
Fig. 7 A is the sectional view that the tissue slice of a kind of embodiment of a kind of tumor tissues and bioartificial organ system is arranged;
Fig. 7 B is the skeleton view that the tumor tissue section of Fig. 7 A arranges;
Fig. 8 utilizes a kind of bioartificial organ system, the graphic representation that external lignocaine is removed under pouring into continuously and intermittently;
Fig. 9 is the graphic representation that external lignocaine is removed, and wherein utilizes bioartificial organ system operation 6 hours and 24 hours;
Figure 10 is the graphic representation of external DMX concentration, wherein utilizes bioartificial organ system operation 6 hours and 24 hours; And
Figure 11 is the graphic representation that external ammonia is removed, and wherein utilizes bioartificial organ system operation 6 hours and 24 hours;
Figure 12 is a synoptic diagram, the technology that its a kind of tumor tissue section equipment that content of the present invention is shown is adopted;
Figure 13 is a kind of operational sequence diagram of embodiment, and its explanation according to the embodiment of the present invention, utilizes tumor tissues and bioartificial organ system to obtain the method for useful consequence.
Detailed Description Of The Invention
As employed in content of the present invention, term " scheme (regimen) " should be managed Separate for one or more medicines of expression, compound, therapeutic agent, nucleic acid, peptide, metabolin, Virus, bacterium or can be applicable to other preparations of cell or tissue.
The present inventor has found a kind of improved combined system, is used for coming automatically Circulating plasma a kind ofly is particularly useful for that tumor tissues detects to form around the slices of organs of thing System.
Another purpose of content of the present invention provides a kind of effective method, wherein utilizes one Plant and be used for before the actual patient who lives with compound, detecting (test) this compound effect The platform of power. The toxicity of compound and pharmacological action are by coming real with external animal experiment in the body Existing. Yet content of the present invention both can utilize tumor tissues also can utilize the people to organize to train Support, and be used for test at this structural compound. For new medical compounds, FDA Can require this novel drugs applicant on minimum level: (1) obtains the pharmacology spy of this medicine The property; (2) determine the acute toxicity of this medicine at least two animal species; And (3) Depend on plan duration and the purposes of material in the clinical research of plan, carried out for 2 weeks Short term toxicity research to 3 months. This process is complexity and expensive, wherein becomes Hundred and thousands of compound is tested sometimes.
The further purpose of content of the present invention provides a kind of method, and is by the method, a kind of Pharmaceutical admixtures (for example a kind of chemotherapy regimen) can carry out personalization to individual user. Logical Normal, in the situation of using chemotherapy regimen, not all scheme in all patients with Same way as work. Effectively drug mixture in another patient will be in a patient Invalid. Content of the present invention provides a kind of method, is used for detection of drugs before giving the patient The effectiveness of scheme, thus only give each patient with the most effective scheme.
The further purpose of content of the present invention provides a research platform and method, is used for disease The research of sick research and the mode of compounds affect tissue (especially utilizing tumor tissues).
For this disclosure content, term tissue sample, histotomy or organize five equilibrium Sample refers to a kind of bioartificial organ system, or is not one one of bioartificial organ system The histiocytic cell culture (especially tumor tissues) that divides.
A kind of embodiment of content according to the present invention provides a kind of tumor tissues detection method, and it uses a kind of bioartificial organ system to estimate, detect and test drug candidate, medicine and drug metabolite (being included in contrast).This system has a kind of neoplasmic tissue slice culture apparatus.Other similar systems that can test tumor tissues and bioartificial organ also obviously are taken into account.In addition, in other embodiments, the method for content of the present invention can be used together with conventional tissue samples.Yet during with people's tissue bond, tumor tissues is the most effective for obtaining real-time conclusion and legitimate reading in detection.
Content of the present invention provides a kind of method that tumor tissues detects that is used for, this method provide a kind of in individual patient the approach (mode) of personalized chemotherapy, to predict toxicity and the study of disease of a kind of compound in healthy tissues.According to a kind of embodiment, during for example examination of living tissue of performing the operation, extract a tissue sample.This sample is cut into a plurality of tissue slicies.Various chemotherapy regimens are applied to each tissue slice.After finishing this scheme, relatively these results are to determine the effectiveness of each scheme.By more various schemes, based on chemotherapy regimen that can design personalized from the result of these tests.Other application of improved detector (as disclosed) are research and estimate toxicity and research and evaluation of tissue pathology.
Fig. 1 is a kind of synoptic diagram of embodiment of a kind of drug testing system 10 of the content according to the present invention.Developing medium (substratum) 13 is introduced in the bio-reactor 15 from storage tank 12.In bio-reactor 15 is at least one tissue slice apparatus 20, and it comprises that at least one is arranged in two tissue slicies 23 (referring to Fig. 7 A and Fig. 7 B) between the gauze 21, and vertically parallel placement in bio-reactor 15.Along with developing medium is introduced in the bio-reactor, culture medium level begins to rise until its contact tissue section, and it makes tissue slice 23 can contact the myriad of compounds of introducing via developing medium.
Those skilled in the art will recognize that storage tank 12 is same interchangeable with a plurality of related solution, mechanism, device and technology.Equally, machine or the instrument of implementing their function can freely exchange with storage tank 12, and do not deviate from the scope of content of the present invention.
Oxidizing gas is introduced by the gas trap 151 at the top, chamber.Although gas trap is illustrated in the top of chamber, this paper considers that also gas trap can be in the side or the bottom of chamber, as long as there is suitable sealing to leak to prevent liquid medium.Gas is the O of 95 volume % preferably
2CO with 5 volume %
2Mixture, and supply to described chamber and, come control pressure by the pressure controller (not shown) simultaneously by gas trap from its release with the pressure in 1 to 10atm scope.One magnetic valve (also not shown) can be connected gaseous tension to keep being scheduled to this pressure controller.One gas sterilizing unit 18 for example has the syringe filter in about 0.22 μ m aperture, is preferably mounted in the gas trap 151, to filter microorganism, thus the gas that supplies to the chamber is carried out disinfection.Gas vacuum breaker 11 with gas sterilizing unit 18 is positioned on the culture medium reservoir and is used for pressure between compensation (balance) storage tank and the atmosphere.
The stabilization of tissue slice (comprising tumor tissues) is a key property of the present invention.Tissue slice is to cultivate under the condition of supplying with substratum and oxidizing gas.Liquid culturing medium or blood plasma are fed in the chamber by storage tank, and supply oxidizing gas by the top of chamber.So that each tumor tissue section alternately is exposed to this medium and is exposed to this gas, its exposure duration compares at about 1: 1 to about 1: 4 scope with the predetermined distance supply for each.Found about 1: 2.5 to about 1: 3.5 ratio be efficiently, and find that the ratio of about 1: 1 or 1: 3 is more effective, naturally be in those skilled in the art's general knowledge horizontal extent although change these parameters.Flowing of pump 19 control developing mediums.Wherein tissue slice alternately is exposed to the speed of gas and developing medium roughly corresponding to metabolic rate.
In content of the present invention, Waymouth MB 752/1 developing medium is preferred for blood plasma.The specific selection of developing medium or blood plasma type is known for those of ordinary skill and can be different because of cell type.In order to prevent central necrosis, gaseous mixture described above is 95%O
2And 5%CO
2Because this mixture can produce oxyradical (it is deleterious for tissue culture cells usually), so must take more care.For example, for the liver sample, the gsh of adding high density and vitamin-E are as oxygen free radical scavenger and oxidation inhibitor, and the foetal calf serum and the L-glutaminate of additional 10% inactivation.
With reference to Fig. 2, it illustrates a kind of embodiment of a kind of tumor tissues and bioartificial organ system 10.Bioartificial organ system 10 comprises the one or more bio-reactors 15 that are arranged in the incubator (temperature and humidity in the surge chamber) 32.Incubator 32 makes the user can regulate the state of bioartificial organ, guarantees that bioartificial organ is exposed to optimal conditions concerning viability in time.Be used for tissue culture suitable incubator system be chosen in this area be know and do not need further narration.
Be arranged in the incubator is one or more bio-reactors 15.Each bio-reactor 15 holds one or more tumor tissue sections or sample.Turner 30 rotates bio-reactor 15 and is respectively applied for wet and dried stage.The wet stage fully is exposed to the time of substratum corresponding to tissue slice.Equally, the stage of doing fully is exposed to the time of gas corresponding to tissue slice.Control module 34 provides an interface that is used to control bioartificial organ system 10 operating parameterss.For example, utilize control module, tumor tissue section is exposed to the time of gas and substratum and can be regulated, and it is roughly corresponding to metabolic rate.Similarly, gas can utilize control module 34 to be regulated to ratio and other necessary operating parameterss of developing medium.As those skilled in the clear, supply gas and substratum in thermostat container 32.
Now forward Fig. 3 to, it illustrates the close-up view of the bio-reactor 15 that is installed in the thermostat container 32.In order to be easy to enter and take out, bio-reactor 15 and turner 30 can be attached to the platform that slips into and skid off thermostat container 32.In the time of in being installed in thermostat container 32, each bio-reactor 15 is connected to gas and culture medium supplies 36 and 38 respectively.Shown in the embodiment of Fig. 3, gas trap 151 (chamber 155 for each tissue slice apparatus has) is connected to gas supply source 36.As shown in Figure 3, manifold system 17 is arranged between gas trap 151 and the gas supply source 36.Gas filter 18 (as previously mentioned) is installed between gas supply source 36 and the gas trap 151.Similarly, culture medium valves 153 is connected to culture medium supplies 38.Culture medium filter 18 (as previously mentioned) is arranged between culture medium supplies 38 and the culture medium valves 153.
Now forward Fig. 4 to, it illustrates a kind of embodiment of bio-reactor 15.Although many structures are utilizable and those skilled in the art are appreciated that but the embodiment shown in Fig. 4 comprises a plurality of neoplasmic tissue slice apparatus chamber 155 (referring to Fig. 5).When bio-reactor seat 157 and bioreactor cover 158 interconnected, each tissue slice apparatus chamber 155 formed by sealed cavity.Gas trap 151 can be connected to gas supply source 36 and gas communication usually in tissue slice apparatus chamber 155, so that provide a certain amount of desired gas mixture for the tissue slice that is contained in the tissue slice apparatus chamber 155.Culture medium valves 153 fluids are communicated in tissue slice apparatus chamber 155, and it is identical for the effect of gas with gas trap 151 for the substratum role.According to some embodiments, bioreactor cover sealer 159 sealing bioreactor cover 158 and bio-reactor seats 157.When bio-reactor seat 157 and bioreactor cover 158 are interconnect fabric, bioreactor cover sealer 159 can be sealing-ring or other allied equipments that prevent escape of liquid, and when upset, the actual selection that is used as the device of bioreactor cover sealer 159 should be understood and be comprehended by those of ordinary skills.
According to a kind of embodiment shown in Figure 5, each neoplasmic tissue slice apparatus chamber 155 is held at least one tissue slice apparatus 20.When not interconnecting, tissue slice apparatus 20 can be inserted in the cavity of the part of formative tissue slice apparatus chamber 155 in bio-reactor seat 157.According to this illustrative embodiments, single tumor tissue section equipment 20 is inserted in each cavity; Yet,, can in single bio-reactor 15, use a plurality of neoplasmic tissue slice apparatus 20 by a plurality of tissue slice apparatus chamber 155 are provided in bio-reactor 15.But, bio-reactor 15 structures that content imagination of the present invention is such, it comprises the neoplasmic tissue slice apparatus chamber 155 of different numbers, and each neoplasmic tissue slice apparatus chamber 155 has the tissue slice apparatus 20 of different numbers.After each tissue slice apparatus 20 was inserted in the neoplasmic tissue slice apparatus chamber 155, bioreactor cover 158 interconnected with bio-reactor seat 157.In case interconnect, bio-reactor 15 usefulness bioreactor cover sealer 159 are sealed.Then, bio-reactor 15 can be put into thermostat container 32 and be connected with culture medium supplies 38, and correspondingly experimentize with gas supply source 36.
As previously mentioned and shown in the embodiment of Fig. 6, neoplasmic tissue slice apparatus 20 can comprise a plurality of gauzes 21.As previously mentioned, gauze 21 can be made by stainless steel or the known other materials of those of ordinary skills.One or more tissue slicies 23 are placed between the adjacent gauze 21 and with tissue slice apparatus clips 24 gauze 21 is clamped together.Those of ordinary skill should be appreciated that the size of tumor tissue section and thickness may be optimized and can be different because of experiment and tissue at each scheme.
According to illustrative embodiments shown in Figure 6, two gauzes 21 form neoplasmic tissue slice apparatus 23.According to illustrative embodiments, tissue slice 23 is arranged on 40% place, bottom of neoplasmic tissue slice apparatus 20.This set of tissue slice 23 in the tissue slice apparatus 20 guarantees that this tissue slice fully is exposed to the circulation of doing and wet.
Fig. 7 A and 7B show the similar embodiment of neoplasmic tissue slice apparatus 20.Comprised two stainless steel gauzes 21, its size can be selected based on the size of chamber.These two gauze preferred parallel are arranged.In one embodiment, gauze has about 0.26mm aperture.And in one embodiment, the extruding gauze is to guarantee consistent planeness.Between the gauze 21 a plurality of tissue slicies 23, as the liver slice of arranging with orderly fashion.These two gauzes are positioned on each side of tumor tissue section and leave enough spaces so that can not crush this tumor tissue section, and fully clamping they so that they can not washed away by developing medium.Although Fig. 7 A and 7B show the tissue slice of fewer relatively purpose between gauze, the effectiveness that should be appreciated that device depends on the number of tissue slice of employing and the size of tissue slice.In addition, although show two gauzes 21, imagination can be used the gauze 21 of any number.If use single gauze 21, then it is so to form surrounding (at least in part) tumor tissue section 23, thereby forms the space and hold them in this space.For example, gauze can form the U type of appropriate sizeization.
The tumor tissue section 23 that uses in content of the present invention can obtain from appropriate source, and this depends on the purposes that this device is estimated.Neoplasmic tissues is taken into account and can exchanges with animal tissues and use.Yet those of ordinary skills recognize the intrinsic benefit of tumor tissues.Tissue slice 23 can have any size or the shape that is suitable for keeping its viability and basic function.In content of the present invention, the thickness that proves effective tissue slice 23 has at about 10 μ m to the interior thickness of about 2,000 mu m ranges.Determine that in concrete experiment, the about 100 μ m extremely thickness of about 500 μ m are effective.
Content of the present invention is ideally suited in the toxicity of detection of drugs and the method for effectiveness.Described detection is to realize that by the ability that tissue slice is exposed to medicine or drug candidate and tissues observed such as a kind of compound of hepatic tissue metabolism wherein compound or its metabolite can be detected.For example, ammonia and lignocaine are that healthy liver can metabolic common compounds.Following examples have illustrated this detection that is applied to liver slice.Those of ordinary skill in the art will recognize the effectiveness of content of the present invention when being applied to other organs.
For test chemotherapeutic regimens on tissue slice or aliquots containig, at least a compound is applied at least one aliquot of tissue in bioartificial organ system.After the scheduled time, collect data in the past.In each experiment, condition can repeat.
In case finish the detection on each tissue slice or aliquots containig, then comparative data.The comparative result of data is convenient to the various application of content of the present invention, comprises for example detecting mitogen activation, cyto-toxicity parameters and histopathology.In case after the data release, for example, these results can be used for being used for the toxicity of given compound of general forecast or multiple compound, or being used for carcinogenesis research for the most effective chemotherapy regimen of patient's preparation.Certainly, can obtain other inference, and the variation that utilizes tissue slice or aliquots containig to experimentize on designing is convenient to derive different information from data.
Fig. 8-11 has proved and has utilized liver slice as the principle of this paper disclosure of tissue sample and the effectiveness of device.The digital proof that in Fig. 8 and Fig. 9, presents bioartificial organ system remove the ability of lignocaine in time.Similarly, Figure 10 illustrates concentration in time increase fully is set, and it has simulated the body physiological process of sample basically.At last, Figure 11 has proved of the present invention being taught in the detoxify ability of aspect of ammonia.The data that present among Fig. 8-11 are not used for limiting or prove instruction of the present invention with the actual result that obtains, and only are used to prove the effectiveness of training centre acquisition of the present invention.Therefore wish that different structures will obtain similar result, it is not the accurate repetition of data provided herein.
Now forward Figure 12 to, it illustrates a kind of embodiment of a kind of method that is used to use the device that this paper discloses.According to a kind of embodiment, bio-reactor 15 is loaded with tumor tissue section 23 and sealing.Bio-reactor 15 can be equal to the embodiment of this paper disclosure or other devices with similar functions.Bio-reactor is connected at least one culture medium reservoir 12, and it accommodates a certain amount of developing medium.Comprise that according to bio-reactor wherein the embodiment of a plurality of tissue slice apparatus chamber 155, different culture medium reservoir can be used for the specific objective supply developing medium sought according to experiment.For example, according to a kind of embodiment, bio-reactor 15 comprises 6 tissue slice apparatus chamber 155 (referring to for example Fig. 5).First Room can wherein not have to supply developing medium under the situation of additive with comparing.The substratum that comprises the compound (as the lignocaine or the ammonia of various concentration) that will be tested on tissue slice 23 can be supplied with in other 5 chambers.Similarly, can be to all or part tissue slice apparatus chamber 155 identical compounds of supply so that have many group results or prevent the obstruction of a certain tissue slice chip device chamber 155 and retrieve test-results.Yet those skilled in the art should understand, can dispose concrete experimental design and strategy with multiple variation.According to some embodiments, strainer 18 can be set between culture medium reservoir 12 and the bio-reactor 15.
After developing medium and gas are supplied to each tissue slice apparatus chamber 155,15 insulation preset times of bio-reactor.Between soak, tissue slice alternately is exposed to developing medium and gas.This can realize in many ways.For example, developing medium and gas can alternately inject and reclaim so that gas or developing medium any one preset time all in tissue slice apparatus chamber 155.Replacedly, bio-reactor 15 can rotate, so that tissue sample alternately is exposed to developing medium and the gas that is contained in simultaneously in the tissue slice apparatus chamber 155.This can be by with the realization of getting off: guarantee that tissue sample 23 only occupies the certain volume of tissue slice apparatus chamber 155, so that it is immersed in the developing medium fully, and fully be exposed to gas by rotation in a kind of shape.Fig. 6 has illustrated a kind of embodiment that reflects this design, and wherein tissue sample 23 occupies 40% tissue slice apparatus 20.The flexible example of other of this design will be understood by those of ordinary skill in the art.
At the difference of experimental session, the sample that can take out developing medium is used for detecting.According to embodiment shown in Figure 12, drainage pump 60 can take out an aliquots containig of developing medium.In case take out, developing medium can be suggested any gas when being caught by bubble trap 70.After this, this developing medium aliquots containig is remained in the processed culture medium reservoir 50 detect.After the detection, then can get back in the bio-reactor 15 or abandon.Be arranged on this intrasystem strainer 18 and keep sterile state.
A kind of embodiment shown in Figure 13 is for example clear to utilize different compounds and material to detect the method for tumor tissues.In this illustrative methods, tissue sample is to extract at intra-operative.Organize preferably tumor tissues.For example, in order to form personalized chemotherapeutic regimens, will organize from taking out to its patient that form personalized scheme.For example, can take out cancerous tissue and be exposed to various cancer therapy drug mixture, the best cocktail of the particular cancers that is detected to be identified for.Similarly, detect in the application, can use tissue from any suitable tumour or animal host in toxicity.According to some embodiments, can use animal tissues at first.Think a kind of compound in zooscopy safe after, then can use neoplasmic tissue sample further to detect the toxicity of this compound or material.
Tissue slice can be provisionally obtains in other operations, or is used for obtaining obtaining in the operational example of tissue sample such as the examination of living tissue in special design.Therefore for personalized chemotherapeutic regimens, tissue must obtain from the patient, need directly obtain tissue sample from the patient in the operating period that irrelevant intra-operative or special design are used for obtaining tissue sample.Other chemosensitivities are used the tissue sample that can utilize other sources according to specified scheme.
According to some embodiments,, obtain the result with the tissue sample of appropriate size when test on tissue sample during all cpds.Such result comprises personalized medicine related matters, belongs to technician's conventional know-how scope, and can demonstrate,prove the 6th at United States Patent (USP) equally, 678,669,6,905,816,6,983,227 and 6,999, No. 607 one of at least in find, its each as full content proposes in this article, be incorporated into this paper by reference clearly.
After taking out tissue sample from the patient, cut into slices or be divided at least one aliquot of tissue.In one embodiment, then, each section or aliquots containig are individually cultivated in tissue slice apparatus chamber 155 and bio-reactor 15 as previously mentioned, as utilize method shown in Figure 12.Use a plurality of, repeated tissue slice makes the researchist can be exposed to compound at organ level by the tissue slice that this is identical with the doctor, and the best variable that wherein works is the scheme that gives.
Analytical results then.Because this best variable is the scheme that gives, so content of the present invention provides a kind of effective tool of estimating each given scheme than other feasible schemes.In addition, described in following examples, because system and method for the present invention is used at tract and tests on the organism level in some cases, therefore, utilize method of the present invention and instrument, investigator and doctor have a kind of strong instrument and assess mitogen activation, cyto-toxicity parameters, histopathology and many other related application on organ, system and organism level.
According to a kind of embodiment, utilize the technology of the present invention, by being used to can to reproduce a system or organism external from the tissue slice of the multiple tissue of a system and with they connections arranged side by side, but provide can the indication body internal procedure the result.Connect (being) by the transfer of substratum, make the investigator can observe the stepwise effects of a scheme various organ samples from a kind of types of organization to next type.
According to similar embodiment, tissue slice or can be arranged in combination in the tissue slice apparatus 20 with multiple from the histological types of tissue slice.Such experiment makes the researchist can control types of organization in the system in vivo in external environment, is used for research and therepic use.Many variablees when effect that apparatus and method of the present invention is used for observation program and effectiveness will be understood by those skilled in the art.Similarly, the whole bag of tricks of the variable in the control volume in the system will cause technician's interest as the strong mode that obtains the result, otherwise lack tumour or impossible these results of acquisition of experimentation on animals.
For example,, a plurality of tumour liver slices are placed bio-reactor 15 safely, so that make the surface-area maximization of the liver slice that is exposed to developing medium according to a kind of embodiment.Exist a kind ofly to be used for optionally developing medium being supplied to tissue slice apparatus chamber and to remove the means of developing medium from it, thus the contact tissue section so that the developing medium in this chamber rises.Developing medium rises in the chamber so that the submergence fully of liver slice quilt.Also can put upside down such process makes substratum break away from tissue slice.Also there are a kind of means that are used to supply a gas to the top, chamber, so that tissue slice alternately is exposed to this gas and developing medium.This work is finished as previously mentioned.In addition, provide a kind of storage tank, be used for when substratum enters and leave the chamber, holding substratum.The preferably thermal conditioning of this chamber.For tumor tissue section, temperature is preferably maintained in the range of from about 36.5 ℃.For rodent tissue slices, be maintained at about between 36 ℃ to 38 ℃.Yet the porcine tissue section is very responsive for temperature fluctuation, so it must remain on 38 ℃ of the pig normal body temperature.
In one embodiment, the doctor's content that can utilize the present invention to instruct is identified for the optimum concn of a cancer patients's chemotherapy drug cocktail.The doctor is to carrying out examination of living tissue and this tissue sample being divided into aliquots containig from patient's cancerous tissue.The doctor is divided into two groups with these aliquots containigs.Utilize first group of active drug mixture of determining for the patient who is studied.Then, utilize second group of aliquots containig to determine the optimum concn of this drug mixture.
Utilize first group of aliquots containig to determine the most effective drug mixture.Aliquot of tissue is carried out foregoing cultivation.Give this aliquot of tissue with the different pharmaceutical mixture.Measure the apoptosis percentage ratio of cancerous tissue in the aliquots containig by the common method of those skilled in the art.Compare with health tissues then and select to induce the drug mixture of greatest degree of apoptosis in the cancerous tissue.
Then, the doctor utilizes second group aliquot of tissue to determine the optimum concn of the drug mixture that will use on cancerous tissue.Aliquot of tissue is cultivated in the mode identical with first group of aliquot of tissue.The doctor uses the drug mixture of different concns to each aliquot of tissue, and the concentration of the drug mixture of selecting to give the cancerous tissue greatest degree of apoptosis of comparing with health tissues.
Because optimize the result of chemotherapy regimen (patient will accept this scheme with the treatment cancer), the patient will accept to give the treatment that maximum benefit minimizes undesirable side effect simultaneously.If the doctor wishes that identical result can obtain in single experiment, wherein the different concns of a plurality of drug mixtures is applied to a plurality of aliquot of tissue.
In another embodiment, instruction of the present invention can be used for the toxicity of predictive compound to health tissues.Such result can be used for producing data and refers to FDA, to pursue the approval of new drug application or simple new drug application.By carrying out examination of living tissue or obtaining animal or neoplasmic tissue sample as a part of performing the operation.Usually use two kinds of animals, a kind of rodent and a kind of non-rodent are because a kind of medicine may be different with the influence to another species to the influence of species.Equally, other organs critical data is provided and in the scope of content of the present invention of great use.In another embodiment, tissue be part available from the organ donor of death, clone, regenerated or provide by technology well known by persons skilled in the art, comprising from the Cord blood to the stem cell, (transplanting) by means of somatocyte.
Aliquot of tissue derives from tissue sample and cultivates as previously mentioned.As previously mentioned, in case cultivated this tissue, then a kind of compound is applied to each aliquot of tissue and obtains the effectiveness of expected result to determine this compound.Press FDA regulation, or collect data and make an explanation according to the parameter that those of ordinary skills set when determining the effectiveness of compound in tissue.
Similarly, in disease research, can utilize all cpds to carry out disease research.For example, the compound inhibitor and the stimulant that can be used in the tissue studied their influences to the chemical paths in the tissue.In addition, compound can be put on tissue and organize on the level to observe them, rather than in the influence of cell levels or organism level.Content of the present invention provides the method for using bioartificial organ system; Experiment parameter is conspicuous and need not over-drastic experiment to those skilled in the art.
Can test by third party independently, so that get rid of the presentation of any deviation.Do everything possible and guarantee the source of the least possible animal, and guarantee they are carried out oncotherapy as tissue sample.Replacedly, content of the present invention also comprises the use of tumor tissues, and the sample of tumor tissues can obtain from organ donor.Because most drug metabolism in liver is so toxicity research concentrates on the influence to liver naturally.
Embodiment 4
The present invention also provides a kind of interactional new mode (approach) between the tract that is used to observe.Tissue slice can obtain from multiple organ.Then, put into a plurality of bio-reactor tissue slice apparatus chamber with these tissue slicies are parallel.Developing medium is applied to first Room and allows contact tissue section for some time.After the initial time section, developing medium is taken out and moves on to second tissue slice apparatus chamber from first tissue slice apparatus chamber, it comprises from Different Organs, or homolog tissue sample of (as the different concns of the metabolism that increases, different primary cell type, the cell type that maybe will study) under different experimental conditions.In some embodiments, before developing medium is moved on to second tissue slice apparatus chamber or simultaneously, the sample that can obtain developing medium is to carry out intermediate detection.Then, allow the developing medium reaction for some time that moves into second tissue slice apparatus chamber.Each tissue slice apparatus chamber is repeated this process to be finished until experiment.
For example, the researchist may be interested in the proteopepsis.Therefore, the sample of tissue can be from the oral cavity, esophagus, stomach, the small intestine part and the large intestine inside that are equivalent to duodenum, jejunum and ileum obtains.Therefore, the sample with developing medium of protein sample can be treated the influence of digestible protein to determine certain organs with each diverse types of organization reaction on system level.
Though by being considered to the most practical at present and preferred embodiment apparatus and method being described, but be to be understood that, this disclosure content does not need to be confined to disclosed embodiment, but cover interior various changes and the similar arrangement of spirit and scope that is included in claim, wherein the scope of claim should be consistent so that contain all such change and similar structures with the wideest explanation.Content of the present invention comprises any of claims and all embodiments.
Claims (10)
1. one kind is utilized tumor tissues to carry out drug testing and method for screening, comprising:
A kind of bio-reactor that is used in external analogue body basically inner tissue function is provided;
Make described bio-reactor hold at least one aliquots containig of tissue sample; And
Make at least one aliquots containig produce useful data.
2. method according to claim 1, wherein, condition is that the interaction between the cell and cell realizes in the described tissue by keeping in the body.
3. method according to claim 1 wherein, is to produce by the combination that utilizes described tissue sample and bio-reactor based on the data of tumor tissues.
4. method according to claim 1, wherein, described bio-reactor be used for following one of at least: toxicity or the study of disease of determining best chemotherapy regimen, a scheme of prediction.
5. method according to claim 1, wherein, in described data description mitogen activation, toxicity research and the histopathology one of at least.
6. method according to claim 1, wherein, described bio-reactor duplicates function of organization in organism level basically.
7. method according to claim 6, wherein, described bio-reactor reappears function of organization in system level basically.
8. method according to claim 7, wherein, described bio-reactor reappears function of organization at organ level basically.
9. method according to claim 1, wherein, described useful data produce by using at least a scheme.
10. one kind is used for the method for work that tumor tissues detects, and it comprises
A kind of system based on bio-reactor is provided, is used to hold tumor tissue section;
The tumor tissues of in described system, packing into based on biological respinse;
In a kind of scheme of described tissue test; And
Collect the result.
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| Application Number | Priority Date | Filing Date | Title |
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| US71296405P | 2005-08-30 | 2005-08-30 | |
| US60/712,964 | 2005-08-30 | ||
| US60/782,029 | 2006-03-13 | ||
| US60/785,308 | 2006-03-23 | ||
| US60/791,966 | 2006-04-14 |
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| ZA (1) | ZA200801831B (en) |
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