ACOUSTICALLY MEDIATED FLUID TRANSFER METHODS AND USES THEREOF

• US 20080103054A1
• Filed: 12/26/2007
• Published: 05/01/2008
• Est. Priority Date: 12/12/2000
• Status: Active Grant

• Current Assignee: Labcyte, Inc. (Danaher Corporation)
• Original Assignee: EDC Biosystems, Inc.
• Inventors: Jutty, Tarlochan, Lee, Lawrence, WILLIAMS, Roger, Mansour, N., Forbush, Michael
• Granted Patent: US 8,137,640 B2
• Time in Patent Office: Days
• US Class Current: 506/7
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00362 Acoustic nozzles
• CPC Class Codes: B01J 2219/00378 Piezoelectric or ink jet dispensers
• CPC Class Codes: B01J 2219/00527 Sheets
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/00596 Solid-phase processes
• CPC Class Codes: B01J 2219/00605 the compounds being directly bound or immobilised to solid supports
• CPC Class Codes: B01J 2219/00612 the surface being inorganic
• CPC Class Codes: B01J 2219/00637 by coating it with another layer
• CPC Class Codes: B01J 2219/00641 the porous medium being continuous, e.g. porous oxide substrates
• CPC Class Codes: B01J 2219/00659 Two-dimensional arrays
• CPC Class Codes: B01J 2219/00725 Peptides
• CPC Class Codes: B01L 2300/0819 Microarrays; Biochips
• CPC Class Codes: B01L 2400/0433 vibrational forces
• CPC Class Codes: B01L 2400/0436 acoustic forces, e.g. surface acoustic waves [SAW]
• CPC Class Codes: B01L 3/0268 using pulse dispensing or spraying, eg. inkjet type, piezo actuated ejection of droplets from capillaries
• CPC Class Codes: B05B 17/0615 spray being produced at the free surface of the liquid or other fluent material in a container and subjected to the vibrations
• CPC Class Codes: C40B 30/04 by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding
• CPC Class Codes: C40B 40/02 Libraries contained in or displayed by microorganisms, e.g. bacteria or animal cells; Libraries contained in or displayed by vectors, e.g. plasmids; Libraries containing only microorganisms or vectors
• CPC Class Codes: C40B 40/04 Libraries containing only organic compounds
• CPC Class Codes: C40B 40/08 : Libraries containing RNA or DNA which encodes proteins, e.g. gene libraries
• CPC Class Codes: C40B 40/10 : Libraries containing peptides or polypeptides, or derivatives thereof
• CPC Class Codes: C40B 50/00 : Methods of creating libraries, e.g. combinatorial synthesis
• CPC Class Codes: C40B 60/14 : for creating libraries
• CPC Class Codes: F04F 7/00 : Pumps displacing fluids by using inertia thereof, e.g. by generating vibrations therein
• CPC Class Codes: G01N 21/11 : Filling or emptying of cuvettes
• CPC Class Codes: Y10T 137/206 : Flow affected by fluid contact, energy field or coanda effect [e.g., pure fluid device or system]
• CPC Class Codes: Y10T 137/2196 : Acoustical or thermal energy
• CPC Class Codes: Y10T 436/2575 : Volumetric liquid transfer

Abstract

Invention methods employ the use of acoustic waves to transfer small amounts of fluid in a non-contact manner. In invention methods, acoustic waves are propagated through a separated pool of a source fluid in such a manner that causes the ejection of a single micro-droplet from the surface of the pool. The droplet is ejected towards a target with sufficient force to provide for contact of the droplet with the target. Because the fluid is not contacted by any fluid transfer device such as a pipette, the opportunities for contamination are minimized. Invention methods may be employed to transfer fluids from an array of source sites to an array of target sites, thereby enabling the precision automation of a wide variety of procedures including screening, and synthesis procedures commonly used in biotechnology.

Claims

1-57. -57. (canceled)

58. A system for acoustically propelling a portion of a volume of a first liquid from a surface of the first liquid, the system comprising

(a) an acoustic liquid deposition emitter configured to provide sufficient acoustic energy to the first liquid to propel said portion from the volume of the first liquid;

and

(b) a first well for holding the first liquid;

(c) wherein the first well is spaced a distance from the acoustic liquid deposition emitter; and

(d) wherein at least one of the acoustic liquid deposition emitter and the first well is movable so that the distance between the acoustic liquid deposition emitter and the first well is variable.

59. A system according to claim 58, wherein the system is configured to maintain a distance between the acoustic liquid deposition emitter and the surface of the first liquid as the volume of the first liquid in the first well decreases.

60. A system according to claim 58, wherein the acoustic liquid deposition emitter is movable to compensate as the level of the first liquid changes in the first well.

61. A system according to claim 58, wherein the well is movable to compensate as the level of the first liquid changes in the first well.

62. A system according to claim 58, wherein the acoustic liquid deposition emitter comprises a piezoelectric transducer that generates the energy and a lens that focuses the energy toward the surface of the first liquid.

63. A system according to claim 58, further comprising a reservoir configured to hold a liquid that transmits the acoustic energy in contact with the acoustic liquid deposition emitter and the first well.

64. A system according to claim 58, further comprising a second well adjacent to the first well, and wherein the first well and the second well are movable so that the second well is positionable in sufficient proximity to the acoustic liquid deposition emitter that the energy from the acoustic liquid deposition emitter propels a portion of a volume of a second liquid from the second well.

65. A system according to claim 64, wherein the first well and the second well form a portion of a multiwell plate.

66. A system for acoustically propelling a portion of a volume of a first liquid from a first well, the system comprising:

(a) an acoustic liquid deposition emitter configured to provide sufficient acoustic energy to the first liquid to propel said portion from the volume of the first liquid; and

(b) a stage for holding the first well;

(c) wherein at least one of the acoustic liquid deposition emitter and the stage is movable so that the distance between the acoustic liquid deposition emitter and the first well is variable.

67. A system according to claim 66, wherein the system is configured to maintain a distance between the acoustic liquid deposition emitter and a surface of the first liquid as the volume of the first liquid in the first well decreases.

68. A system according to claim 66, wherein the acoustic liquid deposition emitter is movable to compensate as the level of the first liquid changes in the first well.

69. A system according to claim 66, wherein the stage is movable to compensate as the level of the first liquid changes in the first well.

70. A system according to claim 66, wherein the acoustic liquid deposition emitter comprises a piezoelectric transducer that generates the energy and a lens that focuses the energy toward the surface of the first liquid.

71. A system according to claim 66, further comprising a reservoir configured to hold a liquid that transmits the acoustic energy in contact with the acoustic liquid deposition emitter and the first well.

72. A system according to claim 66, wherein the stage is configured to hold a second well adjacent to the first well, and wherein the stage is movable so that the second well is positionable in sufficient proximity to the acoustic liquid deposition emitter that the energy from the acoustic liquid deposition emitter propels a portion of a volume of a second liquid from the second well.

73. A system according to claim 72, wherein the first well and the second well form a portion of a multiwell plate.

74. A system for acoustically propelling a portion of a volume of a liquid from a surface of the liquid, the system comprising:

(a) an acoustic liquid deposition emitter configured to provide sufficient acoustic energy to the liquid to propel said portion from the surface; and

(b) a well for holding the liquid at a liquid level;

(c) wherein the well is configured such that the liquid level in the well decreases after said portion of the volume is propelled from the surface.

75. A system according to claim 74, wherein the well forms a portion of a multiwell plate.

76. A system for acoustically propelling a portion of a volume of a liquid from a surface of the liquid, the system comprising

(a) an acoustic liquid deposition emitter configured to provide sufficient acoustic energy to the liquid to propel the droplet from the surface;

and

(b) a well for holding the liquid;

(c) wherein the well is removable from the system.

77. A system according to claim 76, wherein the well forms a portion of a multiwell plate.

78. A system for acoustically propelling a droplet from a surface of a first liquid, the system comprising:

(a) an acoustic liquid deposition emitter configured to provide sufficient acoustic energy to the first liquid to propel the droplet from the surface;

(b) a well for holding the first liquid at a first liquid level; and

(c) an acoustically-transmissive liquid in contact with the acoustic liquid deposition emitter and the well;

(d) wherein the acoustic liquid deposition emitter has a curved surface that contacts the acoustically-transmissive liquid to form a lens which focuses the acoustic energy toward said surface.

79. A method of forming an array of compound sites for identifying properties of chemical or biological compounds, the method comprising

(a) ejecting a liquid from a well using focused acoustic energy,

(b) depositing the ejected liquid at a location on a substrate,

(c) ejecting a subsequent liquid from a subsequent well using focused acoustic energy,

(d) depositing the ejected subsequent liquid at a subsequent location on the substrate, and

(e) repeating steps (c) and (d) to form the array.

80. A method according to claim 79 wherein said liquid and said subsequent liquid comprise oligonucleotides.

81. A method according to claim 79 wherein said liquid and said subsequent liquid comprise polynucleotides.

82. A method according to claim 79 wherein said liquid and said subsequent liquid comprise cells.

83. A method according to claim 79 wherein said liquid and said subsequent liquid comprise proteins.

84. A method according to claim 79 wherein said liquid and said subsequent liquid comprise chemical compounds.

85. A method according to claim 79 wherein said liquid has a surface, and a distance between an acoustic liquid deposition emitter that produces the focused acoustic energy and said surface is adjusted in response to the liquid being ejected from the well.

86. A method according to claim 79 wherein said well and said subsequent well form a portion of a multiwell plate.

87. An array of compound sites formed using a method according to claim 79.

88. A method of determining the presence of a compound in an analyte, said method comprising contacting an array according to claim 87 with said analyte and detecting the presence of said compound at an array site.

89. A non-contact method for transferring small amounts of source fluid, said method comprising propagating an acoustic wave from an acoustic liquid deposition emitter through a removable source fluid containment structure into a pool of a source fluid, wherein:

a) said acoustic liquid deposition emitter is in contact with said source fluid containment structure through a liquid interposed between said acoustic liquid deposition emitter and a first surface of said source fluid containment structure, said liquid transmitting the acoustic wave from the acoustic liquid deposition emitter to the source fluid containment structure,

b) said pool of source fluid is one of a plurality of pools of source fluid on a second surface of said source fluid containment structure that is opposite said acoustic liquid deposition emitter; and

c) said acoustic wave ejects at least one droplet of said source fluid from said pool.

90. A method according to claim 89, wherein said at least one droplet contacts a target after being ejected from the surface of said source fluid.

91. A method according to claim 89, wherein said acoustic liquid deposition emitter comprises a piezoelectric transducer for generation of said acoustic wave.

92. A method according to claim 91, wherein said piezoelectric transducer is mechanically coupled to an acoustic wave channel structure, wherein said acoustic wave channel structure has an acoustic impedance that is greater than the acoustic impedance of said source fluid.

93. A method according to claim 91, wherein said acoustic liquid deposition emitter further comprises a lens for focusing said acoustic wave.

94. A method according to claim 93, wherein said lens is spherical.

95. A method according to claim 93, wherein said lens has an f-value in the range of about 1 to about 4.

96. A method according to claim 89, wherein said at least one droplet has a defined diameter.

97. A method according to claim 96, wherein said defined diameter is in the range of about 1 micrometer to about 1000 micrometers.

98. A method according to claim 96, wherein said defined diameter is controlled by varying one or more of frequency, voltage, and duration of an energy source used to excite a piezoelectric transducer and thereby propagate said acoustic wave.

99. A method according to claim 89, wherein said pool of source fluid is contained within a well having a bottom, sides and an open top for the ejection of said droplet there through.

100. A method according to claim 89, wherein said source fluid containment structure comprises one or more regions of hydrophilicity for containing said plurality of pools of source fluid.

101. A method according to claim 90, wherein said plurality of pools of source fluid is arranged as an array and wherein said target comprises an array of target zones for receiving said droplet.

102. A method according to claim 101, wherein each pool of source fluid in the array comprises a different source fluid.

103. A method according to claim 101, wherein said array of pools of source fluids is contained in an array of source wells, wherein each of said wells comprises a bottom, sides and an open top for the ejection of said droplet there through.

104. A method according to claim 101, wherein a target zone of said array of target zones is positioned opposite a selected source fluid, such that liquid ejected from the selected source fluid contacts said target zone.

105. A method according to claim 103, wherein said method further comprises positioning of said acoustic liquid deposition emitter relative to said array of source wells to provide for user-defined association of said acoustic liquid deposition emitter with a selected source fluid for ejection of at least one droplet therefrom.

106. A method according to claim 105, wherein said positioning is accomplished by computer-controlled translation of said liquid deposition emitter with respect to said array of source wells.

107. A method according to claim 105, wherein said positioning is accomplished by computer-controlled translation of said array of source wells with respect to said liquid deposition emitter.

108. A method according to claim 89, wherein said pool of source fluid comprises one or more source materials.

109. A method according to claim 108, wherein said one or more source materials comprise one or more biological or chemical compounds.

110. A method according to claim 109, wherein said one or more source materials bear a detectable label.

111. A method according to claim 110, wherein said detectable label is fluorescent or radioactive.

112. A method according to claim 109, wherein said one or more biological compounds comprise a nucleic acid, a polypeptide, a eukaryotic cell, a prokaryotic cell, or a combination thereof.

113. A method according to claim 112, wherein said nucleic acid is DNA or RNA.

114. A method according to claim 109, wherein said one or more source materials comprise a mono- or oligonucleotide, or combination thereof.

115. A method according to claim 108, wherein:

said at least one droplet contacts a target after being ejected from the surface of said source fluid; and

said target is functional for binding said one or more source materials.

116. A method according to claim 115, wherein said target bears one or more target materials.

117. A method according to claim 116, wherein said one or more target materials comprise one or more biological or chemical compounds.

118. A method according to claim 117, wherein said one or more biological compounds comprise a nucleic acid, a polypeptide, or a combination thereof.

119. A method according to claim 118, wherein said nucleic acid comprises s DNA or RNA.

120. A method according to claim 90, wherein said target comprises a biological or chemical compound.

121. A method according to claim 89, further comprising detecting the volume or level of source fluid present in said fluid containment structure.

122. A method according to claim 121, wherein said detecting is performed by directing an acoustic wave at said source fluid, receiving a reflection of said acoustic wave, and determining the level of said source fluid based on the characteristics of said reflected acoustic wave.

123. A method according to claim 121, wherein said volume or level is performed by an acoustical detector coupled to a computer, and wherein said computer computes a change in volume or level based on a first signal received from the detector before said ejecting of said droplet, and a second signal received from the detector after said ejecting of said droplet.

124. A non-contact method for transferring small amounts of a source fluid to a separate target structure, said method comprising activating a piezoelectric transducer thereby propagating an acoustic wave through a liquid which is interposed between said piezoelectric transducer and a first surface of a removable source fluid containment structure, wherein:

a) said source fluid is contained as a pool on a second surface of said source fluid containment structure that is opposite said piezoelectric transducer, said pool of source fluid one of a plurality of pools of source fluid on said second surface, and

b) said target is positioned to receive a portion of said source fluid ejected from said pool of source fluid as a result of propagation of said acoustic wave through said source fluid.

125. A method for transferring small amounts of a source fluid from a pool selected from one of a plurality of pools of source fluid located on a first surface of a removable source fluid containment structure, to a separate target structure without physically contacting said source fluid, said method comprising propagating an acoustic wave through said source fluid such that a single droplet of fluid is ejected from the surface of said pool with sufficient energy to bring said droplet into contact with said target, wherein:

a) said acoustic wave is propagated from a piezoelectric transducer,

b) said piezoelectric transducer is in contact with said source fluid containment structure via a liquid interposed between said piezoelectric transducer and a second surface of said source fluid containment structure,

c) said second surface of said source fluid containment structure is opposite said pool, and

d) said target is opposite said surface of said pool.

126. A system for performing non-contact transfer of small amounts of source fluid, comprising:

a source fluid containment structure;

a movable stage, configured to support the source fluid containment structure;

an acoustic liquid deposition emitter in operative contact with the source fluid containment structure;

a liquid interposed between the deposition emitter and the source fluid containment structure;

a fluid level detector for detecting a level or volume of fluid in a source fluid containment structure;

a lens in operative association with the acoustic liquid deposition emitter for focusing an acoustic wave; and

a computer in operable communication with the acoustic liquid deposition emitter for varying one or more of frequency of the acoustic wave;

voltage of an energy source used to excite the acoustic liquid deposition emitter;

duration of an energy source used to excite the acoustic liquid deposition emitter, or location of the stage relative to the acoustic deposition emitter; and

wherein the computer comprises a computer implemented algorithm for adjusting one or more of;

frequency of the acoustic wave;

voltage of an energy source used to excite the acoustic liquid deposition emitter;

duration of an energy source used to excite the acoustic liquid deposition emitter;

or location of the stage relative to the acoustic deposition emitter in response to a change in fluid level or volume detected by the fluid level detector.