WO2022058909A1 - Appareil pour effectuer des expériences in vitro sur un matériau biologique - Google Patents

Appareil pour effectuer des expériences in vitro sur un matériau biologique Download PDF

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Publication number
WO2022058909A1
WO2022058909A1 PCT/IB2021/058415 IB2021058415W WO2022058909A1 WO 2022058909 A1 WO2022058909 A1 WO 2022058909A1 IB 2021058415 W IB2021058415 W IB 2021058415W WO 2022058909 A1 WO2022058909 A1 WO 2022058909A1
Authority
WO
WIPO (PCT)
Prior art keywords
container
cup
lower chamber
retaining element
diverter
Prior art date
Application number
PCT/IB2021/058415
Other languages
English (en)
Inventor
Silvia Scaglione
Maurizio AIELLO
Original Assignee
React4Life S.R.L.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by React4Life S.R.L. filed Critical React4Life S.R.L.
Publication of WO2022058909A1 publication Critical patent/WO2022058909A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M27/00—Means for mixing, agitating or circulating fluids in the vessel
    • C12M27/18—Flow directing inserts
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/34—Internal compartments or partitions
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
    • C12M29/20—Degassing; Venting; Bubble traps
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation

Definitions

  • the present invention relates to a device for carrying out in vitro experiments on biological material comprising a container, inside which container there is a retaining element for said biological material.
  • the retaining element is positioned inside the container so as to create an upper chamber and a lower chamber of said container.
  • the device object of the present invention can be used to carry out different experiments and on any biological material.
  • transdermal tests can be performed on tissue samples, absorption tests and/or viability tests, such as tests to improve the viability of ex vivo tissue, skin culture tests, drug efficacy tests, toxicity tests, etc.
  • Trans-tissue permeation and absorption tests are generally carried out on tissue samples, preferably biopsies, of any thickness or size.
  • the biological material is positioned inside containers in which both the upper chamber and the lower chamber contain liquid.
  • tissue sample is inserted inside a container in which the lower chamber is filled with liquid, while the upper chamber is filled with air, so that the tissue performs the function of an air/liquid interface (ALI).
  • ALI air/liquid interface
  • Such a scenario is used for example for tissue maintenance tests, in which the sample tissue is nourished by the liquid in the lower chamber to better recreate what occurs in human epithelial tissues in vivo (e.g., skin).
  • the present invention preferably, but not exclusively, relates to this second scenario.
  • the risk is that the bubbles form a real air chamber which insulates the tissue below from the liquid present inside the lower chamber.
  • the bubbles should rise towards the top of the lower chamber as soon as they enter the lower chamber, however, even with low flow rates, the bubbles still have a thrust which can cause the ascent and accumulation below the tissue sample being examined.
  • the containers commonly used for in vitro experiments on biological material do not have suitable features to make the bubbles vent in different areas with respect to the parts where the tissue sample is present, for example they do not have sufficient size or, in other cases, vents inside the lower chamber.
  • the present invention achieves the above objects by making a device for carrying out experiments on biological materials as described above, but with features aimed at avoiding the formation of underlying bubbles.
  • a flow diverter insert is included inside the lower chamber, which has diverter walls diverging in the direction of the retaining element and configured so as to intercept the flow of fluid and to divert part thereof in the lateral direction with respect to the retaining element.
  • the peculiar shape of the diverter walls envisages that the bubbles, entering the lower chamber, abut against the walls themselves and are guided towards the upper chamber, in an outer area not occupied by the tissue sample.
  • the flow diverter insert forces the bubbles to move towards the inner side walls of the container, thereby venting upwards, without in any way modifying the benefits for the tissue ensured by the fluidic circulation (mass transport and mechanical-biological stimulation).
  • the diverter insert has an upper base, a lower base and a connecting side wall.
  • the connecting side wall has surfaces diverging from the lower base to the upper base.
  • the bubbles impact at the lower base are guided along the connecting surface and vent above the upper base, so as not to accumulate below the tissue sample.
  • the connecting side wall has concave surfaces, with the concavity facing in the direction of the inner walls of the container.
  • Such an embodiment allows to divert the bubbles with respect to the tissue sample and its peculiar shape simultaneously limits the perturbation of the flow of fluid flowing inside the lower chamber, avoiding problems on the tests to be carried out and/or on the culture of the sample.
  • Such an embodiment further allows to optimize the size of the diverter insert and to facilitate its insertion into the container, as will be described later.
  • the diverter insert has the purpose of diverting the flow of the liquid to avoid the accumulation of bubbles at the sample of biological material.
  • the diverter insert can be made integrally with at least part of the container, for example with the walls of the lower chamber.
  • the diverter insert can have removable fastening means to the container.
  • Such removable fastening means can consist of a plurality of ribs arranged along the lower base of the diverter insert.
  • the ribs cooperate with an appropriate seat included inside the container, so that the elastic deformation of the material forming the ribs is exploited to easily insert/extract the diverter insert inside the container.
  • Such removable fastening means can also be used in combination with a further component belonging to the device object of the present invention, namely the retaining element.
  • a further component belonging to the device object of the present invention namely the retaining element.
  • one of the most important problems of the devices object of the present patent application known in the state of the art is the blocking of the tissue sample.
  • tissue sample in the case of transdermal tests, the tissue sample must in fact be blocked inside the container, so that the fluid present inside the lower chamber does not pass into the upper chamber unless tissue permeability is involved, which allows this passage, i.e., the feature of interest for the test.
  • the device object of the present invention envisages that the retaining element comprises a blocking element of the tissue sample, consisting of a tubular element, which has ribs on the outer walls for the removable fastening.
  • the removable fastening obtained thanks to the elastic deformation of the ribs, obtained through the compression of the ribs against the inner walls of the container, allows the tissue sample to be crushed towards the bottom of the upper chamber, in order to avoid losses of liquid between the lower chamber and the upper chamber.
  • an “o-ring” seal is used between the tissue sample and the bottom of the container.
  • a device for carrying out in vitro experiments on samples of biological material comprising a container within which there is a retaining element of said tissue sample, positioned so as to create an upper chamber and a lower chamber of the container itself.
  • a hydraulic circuit is also included connected at least to the lower chamber, so as to generate a forced flow of fluid inside said chamber.
  • the retaining element comprises the blocking element described above.
  • a peculiar shape of the container in which the lower chamber has a smaller section with respect to the upper chamber, so as to create a narrowing, a sort of step, on which the tissue sample can rest.
  • the blocking element described is not adapted to be used with tissue samples having limited thicknesses, as the pressure of the blocking element on the tissue can deteriorate the tissue itself, especially in the case of use of a sealing/blocking gasket, in particular in the tissue parts in contact with the latter.
  • tearing or ripping of the tissue itself can also occur due to overpressure or vacuums, for example caused in the hydraulic circuit following fluid withdrawals.
  • the present invention envisages using a retaining element comprising a cup-like element, so that the tissue sample is positioned on the bottom of the cup-like element.
  • the cup-like element has a bottom wall consisting of a grid.
  • the presence of the grid allows to use thin tissue samples, as the grid allows to generate a surface tension on the tissue sample which keeps it crushed on the bottom wall of the cup-like element, without the need to use gaskets, avoiding however the generation of liquid losses and leaks between the lower chamber and the upper chamber.
  • the grid generates a surface tension which prevents the underlying liquid from overcoming the grid itself, preventing leakage from the lower chamber to the upper chamber, even in the absence of sealing gaskets.
  • the grid creates an effect which imprisons the fluid due to the surface tension generated, while the fluid, wetting the tissue, generates contact forces which prevent the tissue from floating and detaching from the bottom of the cup-like element itself.
  • the grid allows to overcome the limited seal caused by the absence of the gasket, especially due to increases in pressure coming from the lower chamber.
  • the cup-like element is preferably closed on the sides, in its lower part, the liquid outside the cup-like element can be at a higher level than the bottom of the cup-like element itself, thus generating a pressure difference which may not keep the tissue sample adhered to the bottom wall of the cup-like element, or generate leakage.
  • the grid can be made according to any of the methods known in the state of the art, but the presence of such a grid contributes to increasing the retention of any bubbles which can form below the tissue itself.
  • the presence of the flow diverter insert in combination with the grid is particularly advantageous, as it allows thin tissue samples to be used, without causing fluid leakage and preventing bubbles from accumulating at the tissue sample.
  • the variant described above can have said blocking element inside the cuplike element.
  • the blocking element is particularly difficult to insert and extract, both inside the cup-like element and directly inside the container.
  • an elongated insertion element can be included, adapted to allow the insertion and extraction of the tubular blocking element inside said container or cup-like element.
  • the elongated element has a thread at the end thereof which cooperates with a corresponding thread included on the inner walls of the tubular element.
  • figure 1 a illustrates an external view of the device for in vitro experiments object of the present invention
  • figures 1 b to 1 e illustrate some sections of the device object of the present according to a possible embodiment
  • figure 2 illustrates a perspective view of a possible embodiment of the flow diverter insert belonging to the device object of the present invention
  • figures 3a and 3b illustrate two perspective views of a possible embodiment of the cup-like element belonging to the device object of the present invention
  • figures 4a to 4c illustrate some possible embodiments of the bottom part of the cup-like element of the previous figures
  • figures 5a and 5b illustrate two perspective views of a possible embodiment of the blocking element belonging to the device object of the present invention
  • figure 6 illustrates a possible embodiment of the insertion/extraction element of the blocking element.
  • the device comprises a container 1 inside which there is a retaining element 2 of a tissue sample.
  • the retaining element 2 is positioned inside the container so as to create an upper chamber 11 and a lower chamber 12.
  • Figure 1 c illustrates the container 1 without the presence of the retaining element, which shows that the container 1 has outer walls delimiting an inner chamber 10.
  • the inner chamber 10 is divided into an upper chamber 11 and a lower chamber 12.
  • Figure 1 e shows the container 1 , illustrating part of the retaining element 2 inserted, so as to divide the inner chamber 10 into the upper chamber 11 and the lower chamber 12.
  • such a hydraulic circuit is shown in part, i.e., the delivery 31 and the suction 32 are shown, consisting of tubes connected to the lower chamber 12.
  • a pump Downstream of such tubes a pump can be present which pumps the fluid in the direction indicated by the arrow A.
  • the delivery 31 can become the suction, while the suction 32 can become the delivery, reversing the direction of the fluid.
  • circuit is included connected to the lower chamber 12, but, either alternatively or in combination, such a circuit can also be connected to the upper chamber 12, as illustrated within patent application WO2018130998.
  • the retaining element 2 has the function of supporting the tissue sample from the head and can be included according to various embodiments.
  • the retaining element 2 comprises a cup-like element 21 , which has a bottom wall 210 on which to arrange the tissue sample.
  • the cup-like element 21 further comprises an upper edge which abuts the upper edges of the inner chamber 10 for fastening the cup-like element 21 in position, as illustrated in figure 1 e and as described within patent application WO2018130998.
  • the tissue sample inserted inside the cup-like element 21 is placed on the bottom wall 210 and remains suspended inside the container 1 , thanks to the interaction between the upper edges of the cup-like element 21 and the inner chamber.
  • Figures 3a and 3b illustrate two views of the cup-like element 21 , which show, in particular in figure 3b, that the bottom wall 210 consists of a grid 4.
  • the grid 4 can be made in any manner known in the state of the art, it must have solid elements 41 to support the tissue sample and empty elements 42, to allow the wettability of the sample and, as described above, generate a surface tension which allows to keep the tissue sample crushed towards the bottom wall 210 and avoid leakage of liquid from the lower chamber to the upper chamber.
  • Figures 4a-4c illustrate three possible embodiments of grids 4.
  • the retaining element 2 not only comprises the cup-like element 21 , aimed at keeping the tissue sample suspended, but also comprises a blocking element 22, figure 1 d, aimed at keeping the tissue sample adhered to the bottom wall.
  • the tissue sample is inserted into the cup-like element 21 , which tissue sample is blocked thanks to the presence of the blocking element 22.
  • the element 21 in combination with the element 22 are inserted inside the container 1 , in particular inside the inner chamber 10, to obtain the device illustrated in figure 1 b, complete with all the components.
  • FIG. 5b A view of the blocking element 22 is illustrated in figure 5b and consists of a tubular element 22, which has ribs 221 on the outer walls.
  • Such ribs 221 cooperate with the inner walls of the cup-like element 21 , so as to avoid relative movement between the blocking element 22 and the cup-like element 21 .
  • the outer diameter of the blocking element 22, comprising the ribs 221 is slightly greater than the inner diameter of the cup-like element, so that, once the blocking element 22 is inserted inside the cup-like element 21 , the ribs 221 deform elastically, so as to ensure the removable fastening of the blocking element inside the cup-like element and to prevent the relative movement thereof.
  • Making the blocking element 22 like a tubular element covers a particularly relevant aspect, as it allows the administration of drugs or the like on the tissue sample to be tested.
  • tubular shape facilitates the insertion and extraction of the blocking element 22 inside the cup-like element 21 .
  • the tubular blocking element 22 has a thread 222 in its inner walls adapted to facilitate the extraction/insertion inside the cup-like element 21 .
  • the elongated element 5 has at one end thereof a thread 51 : the elongated element 5 is inserted and screwed inside the tubular blocking element 22, so as to be integral with the latter.
  • the latter is inserted, allows the latter to be stably blocked inside the cup-like element 21 and, at the same time, thanks to the pressure exerted by the bottom wall 223 of the blocking element 22, to permanently block the tissue sample towards the grid 4 of the cup-like element.
  • the elongated element 5 has, at the end opposite the thread 51 , a loop element 52, adapted to facilitate the gripping and screwing of the elongated element 5 itself.
  • the blocking element is not included in combination with the cuplike element 21 , but is directly fastened to the inner walls of the container 1.
  • the blocking element will have a larger diameter than the inner walls of the cup-like element.
  • FIG 5a illustrates in which the blocking element is made in a manner entirely similar to that described above, a tubular element 22, which has ribs 221 , which in this case cooperate with the inner walls of the container 1 and not with the inner walls of the cup-like element.
  • a thread 222 is included.
  • the blocking element of figure 5a is included in combination with an o-ring type gasket, positioned on the bottom wall 223.
  • Figure 5c illustrates a view of the tubular element 22, in which the bottom wall 223 thereof and the housing seat 224 of the gasket, if any, are highlighted.
  • the device object of the present invention includes a flow diverter insert 6, positioned inside the lower chamber.
  • the flow diverter insert 6 is clearly visible in figures 1 b and 2, of which a section and a perspective view are illustrated, respectively.
  • the flow diverter insert 6 has diverter walls, which diverge in the direction of the retaining element 2 and are configured to intercept the flow of fluid and to divert part thereof in a lateral direction with respect to said retaining element 2.
  • the flow diverter insert 6 interposes the flow of fluid entering in the lower chamber 12 through the delivery 31 and exiting through the suction 32.
  • the liquid enters the delivery duct 31 , laps the walls of the diverter insert 6 and exits the suction duct 32, considering the lower chamber 12 filled with liquid.
  • the bubbles slide along the walls of the diverter insert 6 and, thanks to their propensity to move upwards, they settle and vent on the sides of the retaining element 2.
  • the diverter insert 6 has an upper base 61 , a lower base 62 and a connecting side wall 63.
  • the connecting side wall 63 has a concave shape, with the concavity facing in the direction of the inner walls of the container 1 .
  • the connecting wall has a radial narrowing, until reaching a minimum point, and then includes a radial enlargement before connecting to the lower base 62.
  • the lower base 62 has a smaller diameter than the upper base 61 , while the diameter of the upper base 61 has dimensions equal to or greater than the diameter of the bottom wall of the retaining element 2, where the tissue sample is housed.
  • the upper base 61 can have a concave, convex or flat surface, depending on the speed profiles to be obtained below the tissue sample.
  • the diverter insert 6, in particular the lower base 62 is housed inside a special seat obtained in the thickness of the walls of the container 1 .
  • ribs 63 can be included, the elastic deformation of which allows the detachable fastening of the diverter insert 6 inside the container 1 .
  • a possible embodiment of the diverter insert which has as its main object to divert the bubbles entering the lower chamber 11 , to prevent them from coming into contact with the tissue sample. Therefore, such a diverter insert can also consist of a parabolic element, with the concavity facing the retaining element 2 and fastened thereto, so as to form a sort of "shield" of the tissue sample, which diverts the bubbles laterally with respect to the latter. While the invention is susceptible to various modifications and alternative constructions, some preferred embodiments have been shown in the drawings and described in detail.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Biomedical Technology (AREA)
  • Genetics & Genomics (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Sustainable Development (AREA)
  • Microbiology (AREA)
  • Analytical Chemistry (AREA)
  • Clinical Laboratory Science (AREA)
  • Molecular Biology (AREA)
  • Immobilizing And Processing Of Enzymes And Microorganisms (AREA)
  • Materials For Medical Uses (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)

Abstract

Dispositif pour effectuer des expériences in vitro sur du matériel biologique comprenant un conteneur (1), à l'intérieur duquel conteneur (1) se trouve un élément de retenue (2) dudit matériel biologique, ledit élément de retenue (2) étant positionné à l'intérieur dudit conteneur (1) de manière à créer une chambre supérieure (11) et une chambre inférieure (12) dudit conteneur (1), ledit circuit hydraulique étant connecté au moins à la chambre inférieure (12), de manière à générer un écoulement forcé de fluide à l'intérieur de ladite chambre inférieure (12). Un insert de déviation d'écoulement (6) est également inclus à l'intérieur de ladite chambre inférieure (12), ledit insert de déviation (6) ayant des parois de déviation, lesdites parois de déviation divergeant dans la direction dudit élément de retenue (2) et étant conçues de manière à intercepter l'écoulement de fluide et à en dévier une partie dans une direction latérale par rapport audit élément de retenue (2).
PCT/IB2021/058415 2020-09-16 2021-09-15 Appareil pour effectuer des expériences in vitro sur un matériau biologique WO2022058909A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT102020000021847A IT202000021847A1 (it) 2020-09-16 2020-09-16 Dispositivo per l’esecuzione di esperimenti in vitro su materiale biologico
IT102020000021847 2020-09-16

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WO2022058909A1 true WO2022058909A1 (fr) 2022-03-24

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IT (1) IT202000021847A1 (fr)
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002033052A2 (fr) * 2000-10-17 2002-04-25 Deutsches Herzzentrum Berlin Procede de production in vitro de tissu de remplacement biologique vital au moyen de cultures cellulaires et d'un substrat
WO2013085909A1 (fr) * 2011-12-05 2013-06-13 Research Triangle Institute Modèle humain des voies respiratoires comprenant de multiples passages fluidiques
WO2018030958A1 (fr) * 2016-08-10 2018-02-15 1. Agency For Science, Technology And Research Système microfluidique intégré de culture et de test
WO2018130998A1 (fr) * 2017-01-16 2018-07-19 React4Life Srl Bioréacteur et procédé d'utilisation d'un tel bioréacteur

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002033052A2 (fr) * 2000-10-17 2002-04-25 Deutsches Herzzentrum Berlin Procede de production in vitro de tissu de remplacement biologique vital au moyen de cultures cellulaires et d'un substrat
WO2013085909A1 (fr) * 2011-12-05 2013-06-13 Research Triangle Institute Modèle humain des voies respiratoires comprenant de multiples passages fluidiques
WO2018030958A1 (fr) * 2016-08-10 2018-02-15 1. Agency For Science, Technology And Research Système microfluidique intégré de culture et de test
WO2018130998A1 (fr) * 2017-01-16 2018-07-19 React4Life Srl Bioréacteur et procédé d'utilisation d'un tel bioréacteur

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