WO2020026047A1 - Dispositif et procédé de perméabilisation améliorée de cellules biologiques - Google Patents

Dispositif et procédé de perméabilisation améliorée de cellules biologiques Download PDF

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Publication number
WO2020026047A1
WO2020026047A1 PCT/IB2019/055211 IB2019055211W WO2020026047A1 WO 2020026047 A1 WO2020026047 A1 WO 2020026047A1 IB 2019055211 W IB2019055211 W IB 2019055211W WO 2020026047 A1 WO2020026047 A1 WO 2020026047A1
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WO
WIPO (PCT)
Prior art keywords
biological cells
poration
microfluidic channel
biological
cell
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PCT/IB2019/055211
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English (en)
Inventor
Rahul Singh KOTESA
G.K. Ananthasuresh
Siddharth JHUNJHUNWALA
Prosenjit Sen
Original Assignee
Indian Institute Of Science
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Publication of WO2020026047A1 publication Critical patent/WO2020026047A1/fr

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    • 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
    • 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
    • B01L3/502715—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 characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • 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
    • C12M35/00—Means for application of stress for stimulating the growth of microorganisms or the generation of fermentation or metabolic products; Means for electroporation or cell fusion
    • C12M35/04—Mechanical means, e.g. sonic waves, stretching forces, pressure or shear stimuli
    • 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
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics

Definitions

  • the present disclosure relates generally to the field of poration in biological cells.
  • the present disclosure relates to a device and method for inducing enhanced poration of biological cells without significant distortion of the biological cells.
  • Cell membranes are natural barriers to free transport of molecules and particulate matter from an extracellular space (outside) to the intracellular space (inside) a cell. A key challenge in drug-delivery is overcoming this barrier, while maintaining the viability of a cell.
  • a variety of methods exist for intracellular delivery and for forming pores on the cell membrane [M. P. Stewart, A. Sharei, X. Ding, G. Sahay, R. Langer, and K. F. Jensen,“In vitro and ex vivo strategies for intracellular delivery”, Nature, vol. 538, no. 7624, pp. 183-192, Oct. 2016].
  • Cell- poration may be achieved using an electric field [P. E.
  • a general object of the present disclosure is to provide a device for inducing enhanced poration in biological cells.
  • Another object of the present disclosure to provide a device for intracellular delivery, for example of molecules and particulate matter by inducing enhanced poration in biological cells.
  • Another object of the present disclosure is to provide a method for inducingenhanced poration in biological cells.
  • Another object of the present disclosure to provide a method for inducingenhanced poration in biological cells for intracellular delivery, for example of molecules and particulate matter.
  • the present disclosure relates generally to the field of poration induction in biological cells.
  • the present disclosure relates to a device for inducing enhanced poration of biological cells without significant distortion of the biological cells.
  • the present disclosure provides a device for inducing poration in biological cells, said device comprising: at least one first microfluidic channel configured for flow of a fluid medium through a lumen of the at least one first microfluidic channel, said fluid medium comprising biological cells suspended in the fluid medium; and at least one pair of second microfluidic channels configured for flow of air, disposed perpendicular to the at least one first microfluidic channel and facing one another, said at least one pair of second microfluidic channels pressure coupled to the lumen of the at least one first microfluidic channel, wherein flow of air through the at least one pair of second microfluidic channels causes compression of the biological cells flowing in the lumen of the at least one first microfluidic channel to induce poration in the biological cells.
  • the fluid medium comprises any or a combination of molecules and particulate matter, wherein induction of poration in the biological cells enables intracellular delivery of said any or a combination of molecules and particulate matter into the biological cells.
  • one or more first microfluidic channels are placed in the formation of a grid to enable higher throughput of porated biological cells.
  • the microfluidic channels of the device are made of polydimethylsiloxane (PDMS).
  • PDMS polydimethylsiloxane
  • device is bonded to a rigid substrate such as glass and Silicon.
  • the device is fabricated using soft lithography.
  • the present disclosure provides a method for using a device for inducing poration in biological cells, said method comprising the steps of: flowing a fluid medium through a lumen of at least one first microfluidic channel configured on the device, said fluid medium comprising biological cells suspended in the fluid medium; and flowing air through at least a pair of second microfluidic channels disposed perpendicular to the at least one first microfluidic channel and facing one another, said at least one pair of second microfluidic channels pressure coupled to the lumen of the at least one first microfluidic channel, wherein the biological cells flowing I the lumen of the at least one first microfluidic channel are compressed by the flow of air through the at least one pair of second microfluidic channels to induce poration in the biological cells.
  • the fluid medium comprises any or a combination of molecules and particulate matter, wherein induction of poration in the biological cells enables intracellular delivery of said any or a combination of molecules and particulate matter into the biological cells.
  • the present disclosure provides a method for using the claimed device of the present disclosure for inducing poration in biological cells, said method comprising the steps of: flowing a fluid medium through a lumen of at least one first microfluidic channel configured on the device, said fluid medium comprising biological cells suspended in the fluid medium; and flowing air through at least a pair of second microfluidic channels disposed perpendicular to the at least one first microfluidic channel and facing one another, said at least one pair of second microfluidic channels pressure coupled to the lumen of the at least one first microfluidic channel, wherein the biological cells flowing I the lumen of the at least one first microfluidic channel are compressed by the flow of air through the at least one pair of second microfluidic channels to induce poration in the biological cells.
  • the fluid medium comprises any or a combination of molecules and particulate matter, wherein induction of poration in the biological cells enables intracellular delivery of said any or a combination of molecules and particulate matter into the biological cells.
  • FIG. 1 illustrates a schematic representation of a device forinducing enhancedporation in biological cells, in accordance with an exemplary embodiment of the present disclosure.
  • FIG. 2 illustrates a schematic representation of an enlarged portion of the device for intracellular delivery of molecules or particles into a biological cell by inducingenhanced poration in biological cell, showing the cellbeing compressedresulting in enhanced poration in cell and delivery of particles into the cell.
  • FIG. 3 illustrates a representation of a cell wall of a biological cell before introducing cells into the proposed device of the present disclosure.
  • FIG. 4 illustrates a representation of the cell wall of the biological cell after the biological cell is allowed to flow through the proposed device of the present disclosure.
  • FIG. 5 illustrates an exemplary fluorescence image showing a cell wall of an RBC along with 30nm beads at the inlet of the proposed device, where the beads are outside the cells.
  • FIG. 6 illustrates an exemplaryfluorescence imageshowingthe cell wall of the RBCalong with 30nm beads at the outlet of the proposed device, where the beads have entered the cell volume of the RBC.
  • FIG. 7 illustrates an exemplary fluorescence image showing a cell wall of an RBC along with lOOnm beads at the inlet of the proposed device, where the beads are outside the cells.
  • FIG. 8 illustrates an exemplary fluorescence image showing the cell wall of the RBC along with lOOnm beads at the outlet of the proposed device, where the beads have entered the cell volume of the RBC.
  • references below to the“invention” or“disclosure” may in some cases refer to certain specific embodiments only. In other cases, it will be recognized that references to the“invention” or“disclosure” will refer to subject matter recited in one or more, but not necessarily all, of the claims.
  • the present disclosure generally relates to a method for inducingenhanced poration in biological cells.
  • the present disclosure provides a method for inducing enhanced poration in biological cells, the methodcomprising the steps of: flowing a biological cell suspended in a medium through a microfluidic channel; introducing air through channels disposed in relation to the microfluidic channel in a cross-sectional manner, the air being introduced is to the extent to cause the biological cell to compress and thereby inducingenhanced poration in biological cell.
  • the present disclosure provides a method for intracellular delivery of molecules or particulate matterby inducingenhanced poration in biological cells.
  • the present disclosure provides a method for intracellular delivery of molecules or particulate matter, the methodcomprising the steps of causing a cell to compress under the influence of the air to the extent it inducesenhanced poration in the biological cell; and allowing the delivery of molecules or particulate matter into cells.
  • the present disclosure provides a method for intracellular delivery of molecules or particulate matter, the methodcomprising the steps of: flowing a biological cell and molecules or particulate matterto be delivered suspended in a medium through a microfluidic channel; introducing air through channels disposed facing each other and in a cross-sectional manner in relation to the microfluidic channel, the air being introduced is to the extent to cause the biological cell to compress thereby inducingenhanced poration, and allowing the delivery of molecules or particulate matter into the biological cell.
  • the present disclosure provides a method for intracellular delivery of molecules or particles into the biological cell ranging from a few angstroms in size to > 100 nm in size into cells without cell lysis.
  • the present disclosure provides a device for inducing enhanced poration in biological cell.
  • a device for inducing enhanced poration in biological cell comprising: a microfluidic channel configured to allow the flow of the biological cell suspended in a medium through the lumen of said microfluidic channel; at least a set of microfluidic channels disposed facing each other and in a cross- sectional manner in relation to the microfluidic channel allowing flow of the biological cell; wherein the set of microfluidic channels are adapted to allow introducing air into the microfluidic channel to the extent causing the biological cell flowing inside the lumen of said microfluidic channel to compress and thereby inducingenhanced poration in the biological cell.
  • FIG. 1 illustrates a schematic representation of a device for inducing enhanced poration in biological cells, in accordance with an exemplary embodiment of the present disclosure.
  • the device (100) comprises: a microfluidic channel (110) configured to allow the flow of the biological cell suspended in a medium through the lumen of said microfluidic channel (110); at least a set of microfluidic channels (120) and (130) disposed facing each other and in a cross-sectional manner in relation to the microfluidic channel (110); wherein the set of microfluidic channels (120) and (130) are adapted to introduce air into the microfluidic channel (110) to the extent causing the biological cell (not shown in figure) flowing inside the lumen of microfluidic channel (110) to compress and thereby inducingenhanced poration in the biological cell.
  • the present disclosure provides a devicefor intracellular delivery of molecules or particulate matter into the biological cellby inducing enhanced poration inthe biological cell.
  • the present disclosure provides a device for intracellular delivery of molecules or particulate matter into the biological cell, the device comprising: a microfluidic channel configured to allow the flow of the biological cell suspended in a medium through the lumen of said microfluidic channel; at least a set of microfluidic channels disposed facing each other and in a cross-sectional manner in relation to the microfluidic channel allowing flow of the biological cell; wherein the set of microfluidic channels are adapted to introduce air into the microfluidic channel to the extent causing the biological cell flowing inside the lumen of said microfluidic channel to compress and thereby inducingenhanced poration in the biological cell; and allowing delivery of the molecules or particulate matter into the biological cell.
  • FIG. 2 illustrates a schematic representation of an enlarged portion of the device for intracellular delivery of molecules or particles into a biological cell by inducing enhanced poration in biological cell, showing the cell being compressed resulting in enhanced poration in cell and delivery of particles into the cell.
  • a microfluidic channel (110) configured to allow flowing a biological cell and molecules or particulate matterto be delivered suspended in a medium through the lumen of said microfluidic channel (110
  • FIG. 3 illustrates a representation of a cell wall of a biological cell before introducing cells into the proposed device of the present disclosure.
  • the pores in the biological cell can be seen to allow only small sized particles to enter the cell volume.
  • FIG. 4 illustrates a representation of the cell wall of the biological cell after the biological cell is allowed to flow through the proposed device of the present disclosure.
  • FIG. 5 illustrates an exemplary fluorescence image showing a cell wall of an RBC along with 30nm beads at the inlet of the proposed device, where the beads are outside the cells.
  • RBCs and 30nm beads are suspended in the buffer at the inlet of the channels, where the beads are outside the cells.
  • FIG. 6 illustrates an exemplary fluorescence image showing the cell wall of the RBC along with 30nm beads at the outlet of the proposed device, where the beads have entered the cell volume of the RBC. As can be seen the 30 nm beads have occupied entire cell volume without shape of the RBC being distorted.
  • FIG. 7 illustrates an exemplary fluorescence image showing a cell wall of an RBC along with lOOnm beads at the inlet of the proposed device, where the beads are outside the cells.
  • RBCs and lOOnm beads are suspended in the buffer at the inlet of the channels, where the beads are outside the cells.
  • FIG. 8 illustrates an exemplary fluorescence image showing the cell wall of the RBC along with lOOnm beads at the outlet of the proposed device, where the beads have entered the cell volume of the RBC. As can be seen the 100 nm beads have occupied entire cell volume without shape of the RBC being distorted.
  • the present disclosure provides a devicefor intracellular delivery of molecules or particles ranging from a few angstroms in size to > 100 nm in size into cells through inducing enhanced poration inthe biological cell, without significant distortion of the biological cell.
  • the extent to which the air is introduced through the set of microfluidic channels can be varied to compress the biological cell to achieve poration of desired dimensions or allowing the delivery of molecules or particles > 100 nm in size into the biological cell without causing cell lysis.
  • the extent of air introduced through the set of microfluidic channels can be controlled with the help of various means, tools, and/or techniques capable of achieving the same.
  • the device can be in the form of system comprising of grid of microfluidic channel configured to allow flow of the biological cell suspended in a suitable medium and sets of microfluidic channels facing each other and disclosed in cross-sectional manner in relation to the microfluidic channel allowing the flow of the biological cells and molecules or particles suspended in a suitable medium to induce enhanced poration in biological cell, for example for intracellular delivery of molecules or particles of interest into the cell.
  • the disclosed device can be made of any material or combination of materials suitable for use in providing microfluidic channels that can allow biological cells to pass through the microfluidic channels.
  • the device can be made of a silicon, glass or polymeric material.
  • the microfluidic system can be made of polydimethylsiloxane (PDMS).
  • PDMS polydimethylsiloxane
  • the device including channels can be fabricated using micro-fabrication techniques such as, but not limited to, soft lithography.
  • the fabricated device may be bonded onto a rigid supporting substrate like glass, silicon or the like.
  • the microfluidic channels can have suitable dimensions so as to allow the flowing of the biological cell through the lumen of the microfluidic channel configured for said purpose and the allow introducing air through the set of microfluidic channels adapted for said purpose.
  • the method and device of the present disclosure is able to induceporation inthe biological cells at high throughput, higher efficiency and larger pore size ( ⁇ / > 100 nm) than what is demonstrated until now.
  • the present disclosure provides a device for inducing enhanced poration in biological cells.
  • the present disclosure provides a device for intracellular delivery, for example of molecules and particulate matter by inducing enhanced poration in biological cells.
  • the present disclosure provides a method for inducing enhanced poration in biological cells.
  • the present disclosure provides a method for inducing enhanced poration in biological cells for intracellular delivery, for example of molecules and particulate matter.

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Abstract

La présente invention concerne un procédé pour induire une perméabilisation améliorée dans des cellules biologiques, comprenant : l'écoulement d'une cellule biologique en suspension dans un milieu à travers un canal microfluidique; l'introduction d'air à travers des canaux disposés par rapport au canal microfluidique de manière transversale, l'air étant introduit dans une telle mesure qu'il provoque la compression de la cellule biologique et ainsi l'induction d'une perméabilisation améliorée dans la cellule biologique. La présente invention concerne en particulier un procédé de délivrance intracellulaire de molécules ou de matière particulaire par induction d'une perméabilisation améliorée dans une cellule biologique. La présente invention concerne en outre un dispositif d'induction d'une perméabilisation améliorée dans une cellule biologique, plus particulièrement pour la délivrance intracellulaire de molécules ou de particules dans la cellule, en particulier de taille > 100 nm.
PCT/IB2019/055211 2018-07-30 2019-06-20 Dispositif et procédé de perméabilisation améliorée de cellules biologiques WO2020026047A1 (fr)

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Cited By (1)

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US11788050B2 (en) 2020-11-18 2023-10-17 Cellfe, Inc. Methods and systems for mechanoporation-based high-throughput payload delivery into biological cells

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11788050B2 (en) 2020-11-18 2023-10-17 Cellfe, Inc. Methods and systems for mechanoporation-based high-throughput payload delivery into biological cells

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