[go: up one dir, main page]

WO2021009201A1 - Dispositif microfluidique - Google Patents

Dispositif microfluidique Download PDF

Info

Publication number
WO2021009201A1
WO2021009201A1 PCT/EP2020/069954 EP2020069954W WO2021009201A1 WO 2021009201 A1 WO2021009201 A1 WO 2021009201A1 EP 2020069954 W EP2020069954 W EP 2020069954W WO 2021009201 A1 WO2021009201 A1 WO 2021009201A1
Authority
WO
WIPO (PCT)
Prior art keywords
microfluidic device
insert
membrane
cover plate
pores
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP2020/069954
Other languages
English (en)
Inventor
Dirk Cornelis VAN GENT
Roland Kanaar
Maayke Maria Petronella KUIJTEN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Erasmus University Medical Center
Original Assignee
Erasmus University Medical Center
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 Erasmus University Medical Center filed Critical Erasmus University Medical Center
Publication of WO2021009201A1 publication Critical patent/WO2021009201A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502761—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
    • 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
    • C12M23/02—Form or structure of the vessel
    • C12M23/16—Microfluidic devices; Capillary tubes
    • 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
    • C12M23/22—Transparent or translucent parts
    • 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
    • C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
    • C12M25/02—Membranes; Filters
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0668—Trapping microscopic beads
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0681—Filter
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/069—Absorbents; Gels to retain a fluid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0848—Specific forms of parts of containers
    • B01L2300/0851—Bottom walls
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0877—Flow chambers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0887—Laminated structure

Definitions

  • the present invention relates to a microfluidic device, an insert for such a microfluidic device and a method of using such a microfluidic device.
  • Microfluidic devices are well known, and are used in many diagnostic and research applications.
  • the present invention seeks to provide an improved microfluidic device compatible with real-time microscopic imaging and especially suitable for use with three dimensional cell structures such as organoids and spheroids.
  • a microfluidic device is provided, in accordance with the claims as appended. Furthermore, in a further aspect, the present invention relates to methods of using such a microfluidic device, e.g. wherein the microfluidic device is applied for a real-time imaging application.
  • Fig. 1 shows a cross sectional view of a microfluidic device according to an embodiment of the present invention
  • Fig. 2 shows a perspective view of an insert for use in a microfluidic device in accordance with a further embodiment of the present invention
  • Fig. 3A and 3B shows a cross sectional view of two embodiments of the insert as shown in Fig. 2;
  • Fig. 4 shows a partial cross sectional view of a microfluidic device according to a further embodiment of the present invention.
  • Fig. 5 shows a perspective view of an optical window of an exemplary embodiment of the microfluidic device of the present invention.
  • the present invention embodiments are related to a microfluidic system, especially suited for three dimensional cell structures such as organoids, organotypic (tissue) slices, biopsies, etc. compatible with confocal imaging.
  • a microfluidic device is provided as well as methods suitable to culture primary tumor material for extended culture periods (days to months) ex vivo, enabling real-time (live) imaging and functional pathology.
  • the technology of (tumor) organoid cultures has great potential for especially drug screening purposes.
  • Organoids may be less suitable for prognostic purposes due to time between biopsy and required clinical decision, and selective advantage of faster growing cells in the material used to derive the organoid.
  • Viable organotypic slices obtained from (primary) tumors from cancer patients, or spheroids/organoids derived from such tumor slices, can provide a suitable alternative approach.
  • the present invention embodiments relate to techniques to culture thin tumor slices ex vivo. It has been shown that these materials can be used in "functional" pathology, because a functional response to therapies can be measured. This will become of great importance in precision (personalized) medicine approaches.
  • the next frontier in this development is to include various aspects of the tumor microenvironment. This can be achieved by e.g. incubating the thin tumor slices ex vivo in microfluidic devices. It is also possible to build tumor like structures by co-culture of various cell types (immune cells, blood vessel endothelial cells, microbiome) in microfluidic devices.
  • a microfluidic chip device that can accommodate long-term culture of tumor slices ex vivo, suitable for diagnostic procedures and integration into clinical practice.
  • the microfluidic device embodiments as described herein have great potential to be applied in clinical practice for diagnostic purposes, not only for breast cancer, but virtually any (solid) tumor type.
  • the present invention embodiments are e.g. provided as a Cancer-On-Chip (CoC) facility, which will not only allow extended culturing of tumor tissue ex vivo, but also development of models for immunotherapy, as (immune) cells can be introduced in a controlled fashion.
  • CoC Cancer-On-Chip
  • CoC systems can also be imaged microscopically in real-time, which will be of great value to follow various processes in real-time (for example, DNA damage response and apoptosis).
  • the present invention relates to methods of using such a microfluidic device, e.g. wherein the microfluidic device is applied for a real-time imaging application.
  • Fig. 1 shows a cross sectional view of a microfluidic device 1 according to an embodiment of the present invention.
  • the microfluidic device 1 is arranged for holding three dimensional cell structures 2, such as organoids, spheroids, tissue samples, organotypic slices, etc.
  • the microfluidic device 1 comprises a top cover plate 3 (with thickness tt), a bottom cover plate 4 (with thickness tb), and an insert 5 having a membrane 6 provided in an aperture in the insert 5 and extending in a plane of the insert 5.
  • the insert is positioned between the top cover plate 3 and bottom cover plate 4 to form two flow channels 3a; 4a on either side of the insert 5.
  • This arrangement allows to obtain a laminar flow of fluids in the two flow channels 3a, 4a having respective channel heights hi , ti2 of e.g. 250pm. It is noted that by using different heights hi , h ⁇ in the flow channels 3a, 4a, the fluid volume above and below the insert 5 and membrane 6 can be made different.
  • the fluids can be entered into the flow channels 3a, 4a, using flow channel inputs 3b, 4b, and can be extracted at the other ends of the flow channels 3a, 4a, e.g. using flow channel outputs 3c, 4c. This can be accomplished e.g. using pump and control set-ups of microfluidic arrangements which are known as such.
  • the flow channels 3a, 4a are sealed using separate seal elements 8. It is noted that in the microfluidic device 1 , the three dimensional cell structures 2 positioned in pores 6a of the membrane 6 are embedded in a hydrogel 7, allowing interaction with the fluid in the two flow channels 3a, 4a.
  • the membrane 6 is provided with a plurality of pores 6a for holding three dimensional cell structures, with a pore size of at least 50pm.
  • the pore size is larger than pore sizes in prior art microfluidic devices having an arrangement with an insert having a membrane, allowing to adequately position and hold the three dimensional cell structures 2 as mentioned above.
  • an insert 5 is provided for use in a microfluidic device 1 according to any one of the microfluidic device embodiments described herein.
  • Fig. 2 shows a perspective view of such an insert 5 for use in a microfluidic device 1 , the arrows indicating the general direction of flow of a fluid in the (upper) flow channel 3a.
  • a method is provided of using a microfluidic device 1 according to any one of the present invention embodiments, comprising feeding a first fluid in a first flow channel 3a between the insert 5 and the top cover plate 3, and feeding a second fluid in a second flow channel 4a between the insert 5 and the bottom cover plate 4.
  • the first fluid can be the same as the second fluid, but alternatively, the first fluid is different from the second fluid.
  • the method may further comprise adding an imaging agent to the second fluid, e.g. for influencing a refractive index.
  • This imaging agent can be advantageous when using the microfluidic device 1 for (confocal) imaging, such as agents to increase refractive index of fluids such as iodixanol.
  • the pore size of the individual pores 6a is at least 100pm, e.g. at least 250pm. This allows to accommodate even bigger three dimensional cell structures 2 in operation.
  • the pore size of the pores 6a can even be as high as 400pm.
  • the pores 6a in the membrane 6 can be provided in a specific pattern, e.g. in a specific embodiment the plurality of pores 6a comprises an array of at least two by at least two pores (6a).
  • the array of cells can alternatively be a 3x3 array, 3x4 array, 4x4 array, etc., etc.
  • the array configuration and pore size can e.g. be adapted to the specific three dimensional cell structures 2 for which the microfluidic device 1 is being used, as the requirements in this respect can be different for organoids, spheroids and organotypic slices.
  • Advantageous combinations are e.g. a 2x2 array of 400pm pores 6a, or a 3x4 array of 250pm pores 6a.
  • the membrane 6 is positioned symmetrical in the insert 5. This allows to have a symmetrical contact of the three dimensional cell structures 2 with the fluids in the flow channels 3a, 4a via the respective hydrogel 7 layers.
  • the membrane 6 is an integral part of the insert 5, and can be manufactured as an integrated body, a single piece body, and can then be used as a one piece disposable item, greatly enhancing usability of the insert 5 and/or microfluidic device 1 (low cost and easy to handle).
  • the membrane 6 can be a separate item, affixed in an aperture in the insert 5, e.g. using glue or other fixation means.
  • the membrane 6 has a dimension of 10x10mm in a further embodiment, e.g. in combination with insert 5 dimensions of 45 x 15 mm.
  • the membrane 6 is advantageous if the membrane 6 is a sunken part of the insert 5, e.g. with symmetric depths on both sides of the membrane 6 (of e.g. 0.8mm).
  • Fig. 3A shows a cross sectional view of the insert embodiment of Fig. 2 with some exemplary detail dimensions. As shown in this exemplary embodiment (not to scale), the membrane
  • the membrane 6 has a thickness t m which is less than a thickness t, of the insert 5, and a hydrogel material 7 is provided on (both sides of) the membrane 6.
  • the membrane thickness t m is e.g. 10pm
  • the insert thickness t is e.g. 0.8mm.
  • the material of the membrane 6 is advantageously a biocompatible material, having as little as possible or no interference with (multiphoton or confocal) imaging of the three dimensional cell structures 2 in the microfluidic device 1 .
  • the material of the hydrogel 7 is e.g. a polyethylene glycol (PEG) based hydrogel, or a polyethylene glycol diacrylate (PEGDA) based hydrogel, which has the advantage that no cell adhesion occurs from the three dimensional cell structures 2. Furthermore, the hydrogel
  • the insert 5 further comprises a secondary membrane layer 6b (below or above the‘primary’ membrane 6) having a plurality of secondary pores with a smaller dimension than the pores 6a of the primary membrane 6, e.g. less than 20pm (e.g. about 8pm).
  • This secondary membrane 6b may in an even further embodiment be provided with a coating layer on both sides, of the same or different coating material.
  • the combination of the primary membrane 6 and secondary membrane 6b in the insert 5 in this group of embodiments would allow to form special 3D cell culture models such as spheroids with a cell monolayer (e.g. endothelial cells to mimic a blood vessel).
  • a cell monolayer e.g. endothelial cells to mimic a blood vessel.
  • the secondary membrane 6b with small pore sizes (around 8pm) to form a cell monolayer, and use the primary membrane 6 on top of the secondary membrane 6b to form the spheroids directly in this insert.
  • no intermediate transfer is necessary to form such special 3D cell culture models.
  • This embodiment can be further enhanced using a spatial patterning of cell-adherent and cell-repellent materials to guide formation of spheres 2 on specific positions of the primary membrane 6 and/or secondary membrane 6b.
  • two membranes of different structure (such as the primary membrane 6 and secondary membrane 6b) are combined in a single insert 5.
  • microfluidic device 1 embodiments described herein are made of biocompatible materials. Furthermore, the structure and materials used are compatible with X-ray exposure, i.e. there will be no issues with radiation absorption, and also compatible with use of a (confocal) microscope.
  • the bottom cover plate 4 comprises a transparent material.
  • the transparent material e.g. comprises glass, or an optically transparent polymer, such as a cyclic olefin copolymer (COC).
  • COC cyclic olefin copolymer
  • the bottom cover plate 4 has a thickness (tb) of less than 0.3mm, e.g. less than 0.2mm, e.g. 0.17mm, in a further embodiment.
  • Fig. 4 shows a partial cross sectional view of a microfluidic device 1 according to an even further group of exemplary embodiments of the present invention.
  • the bottom cover plate 4 comprises an optical window 9.
  • the optical window 9 may comprise the same material as the bottom cover plate 4, but alternatively comprises an optically special material.
  • the bottom cover plate 4 may be of a glass material specifically arranged to provide sufficient strength to prevent breaking of the microfluidic device 1 , while the optical window 9 comprises an optically optimized material.
  • the optical window 9 has a thickness of less than 0.3mm, e.g. less than 0.2mm, e.g. 0.17mm, whereas the bottom cover plate 4 can then have a larger thickness.
  • the thickness of the optical window 9 may be smaller than the thickness tb of the bottom plate 4, and the optical window 9 may be positioned flush with the bottom side of the bottom plate 4, flush with the bottom channel 4a, or at an intermediate position.
  • the optical window 9 is provided as an optical waveguide assembly, comprising cladding material 9a with a first refractive index, and one or more cores 9b with a material having a second refractive index.
  • the one or more cores 9b can then be aligned with the pores 6a of the membrane 6 above the optical window 9.
  • the optical waveguide assembly with cladding material 9a and cores 9b is positioned on top of optical window 9, i.e. within the bottom channel 4a of the microfluidic device 1 .
  • the size and position can be aligned with the circumference of the plurality of pores 6a of the membrane 6.
  • the number of cores 9b is larger than the number of pores 6a, allowing the pores 6a in the (primary) membrane to be aligned with multiple cores 9b.
  • the optical window 9 as described in the previous paragraph will solve this problem, as light is able to travel through the one or more cores 9b more efficiently.
  • the optical window 9 is provided as a plate or block of e.g.
  • Such an optical window 9 can be prepared using a mold to pore the agarose material 9a to make the optical window 9 with slots for the smaller cores 9b, and when cooled the hydrogel material can be poured in these slots, and allowed to solidify.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Clinical Laboratory Science (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Genetics & Genomics (AREA)
  • Sustainable Development (AREA)
  • Dispersion Chemistry (AREA)
  • Immunology (AREA)
  • Physics & Mathematics (AREA)
  • Fluid Mechanics (AREA)
  • Analytical Chemistry (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)

Abstract

L'invention concerne un dispositif microfluidique destiné à contenir des structures cellulaires tridimensionnelles (2), comportant une plaque de recouvrement supérieure (3), une plaque de recouvrement inférieure (4), et un insert (5) ayant une membrane (6) située dans une ouverture dans l'insert (5) et s'étendant dans un plan de l'insert (5). En fonctionnement, l'insert (5) est positionné entre la plaque de recouvrement supérieure (3) et la plaque de recouvrement inférieure (4) pour former deux canaux d'écoulement (3a; 4a) de part et d'autre de l'insert (5). La membrane (6) est pourvue d'une pluralité de pores (6a) destinés à contenir des structures cellulaires tridimensionnelles, avec une taille de pore d'au moins 50 pm. Le dispositif microfluidique (1) peut être appliqué pour une application d'imagerie en temps réel.
PCT/EP2020/069954 2019-07-15 2020-07-15 Dispositif microfluidique Ceased WO2021009201A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP19186226 2019-07-15
EP19186226.7 2019-07-15

Publications (1)

Publication Number Publication Date
WO2021009201A1 true WO2021009201A1 (fr) 2021-01-21

Family

ID=67297014

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2020/069954 Ceased WO2021009201A1 (fr) 2019-07-15 2020-07-15 Dispositif microfluidique

Country Status (1)

Country Link
WO (1) WO2021009201A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004101743A2 (fr) * 2003-05-06 2004-11-25 Bellbrook Labs, Llc Cultures cellulaires tridimensionnelles dans un systeme de manipulation fluidique a petite echelle
US20050164377A1 (en) * 2001-10-31 2005-07-28 Tomoyuki Miyabayashi Base material for culturing embryo stem cells and culture method
WO2017070542A1 (fr) * 2015-10-22 2017-04-27 The Trustees Of The University Of Pennsylvania Systèmes et procédés de production de modèles micro-façonnés du col de l'utérus humain

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050164377A1 (en) * 2001-10-31 2005-07-28 Tomoyuki Miyabayashi Base material for culturing embryo stem cells and culture method
WO2004101743A2 (fr) * 2003-05-06 2004-11-25 Bellbrook Labs, Llc Cultures cellulaires tridimensionnelles dans un systeme de manipulation fluidique a petite echelle
WO2017070542A1 (fr) * 2015-10-22 2017-04-27 The Trustees Of The University Of Pennsylvania Systèmes et procédés de production de modèles micro-façonnés du col de l'utérus humain

Similar Documents

Publication Publication Date Title
Khoo et al. Expansion of patient-derived circulating tumor cells from liquid biopsies using a CTC microfluidic culture device
US9739699B2 (en) Device for the study of living cells
EP2613882B1 (fr) Capsule microfluidique
US8372358B2 (en) Microfluidic system and method for using same
ES2352344T3 (es) Dispositivo de microfluido para estudio de células.
Weinhausen et al. Microfluidic devices for X-ray studies on hydrated cells
US11566224B2 (en) Dendritic cell generator
JP6845228B2 (ja) インビトロ３ｄ細胞培養実験のためのマイクロ流体デバイス
US9975118B2 (en) Device for the study of living cells
Sala et al. Microfluidic lab-on-a-chip for studies of cell migration under spatial confinement
WO2009095666A1 (fr) Microtranchée et test de prolifération tumorale
CN116948823A (zh) 用于异质性细胞培养及监测的微流控芯片及其制备方法
WO2021009201A1 (fr) Dispositif microfluidique
TWI463011B (zh) 細胞自組裝陣列晶片及其製作方法
JP4679847B2 (ja) 細胞の解析方法
WO2020226519A1 (fr) Dispositif microfluidique magnétique pour criblage à haut débit
Lipreri et al. A customizable micropatterned platform for osteosarcoma spheroid generation, imaging, and drug screening
US11547999B2 (en) Cell chip and dynamic dialysis staining for cells
Tan et al. Controlled microscale diffusion gradients in quiescent extracellular fluid
JP6439115B2 (ja) 組織片の機能を発現・維持する方法
Bertani et al. Kinetic Detection of Apoptosis Events Via Caspase 3/7 Activation in a Tumor-Immune Microenvironment on a Chip
US20230392104A1 (en) Cell Culture Carrier
CN119657241B (zh) 抑制癌细胞血管渗透性的药物筛检装置及药物筛检方法
Jang et al. Traction microscopy integrated with microfluidics for chemotactic collective migration
EP3175921A1 (fr) Dispositifs biophotoniques et procédés de leur utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20739690

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20739690

Country of ref document: EP

Kind code of ref document: A1