Apparatus and methods for simultaneous operation of miniaturized reactors

• US 7,507,579 B2
• Filed: 04/01/2004
• Issued: 03/24/2009
• Est. Priority Date: 05/01/2002
• Status: Expired due to Fees

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Zhang, Zhiyu, Zanzotto, Andrea, Boccazzi, Paolo, Chen, Angela Y., Szita, Nicolas, Jensen, Klavs F.
• Primary Examiner(s): Beisner; William H
• Assistant Examiner(s): BOWERS, NATHAN ANDREW
• Application Number:
  US10/816,046
• Publication Number:
  US 20050089993A1
• Time in Patent Office: 1,818 Days
• Field of Search: 435/288.7, 435/303.1, 435/809, 435/808, 435/294.1, 435/297.5, 435/287.5, 382/129, 382/133
• US Class Current: 435/297.5
• CPC Class Codes: B01F 33/30 Micromixers
• CPC Class Codes: B01F 33/453 using supported or suspended stirring elements
• CPC Class Codes: B01J 2219/00283 Reactor vessels with top opening
• CPC Class Codes: B01J 2219/00317 Microwell devices, i.e. having large numbers of wells
• CPC Class Codes: B01J 2219/00479 Means for mixing reactants or products in the reaction vessels
• CPC Class Codes: B01J 2219/00481 by the use of moving stirrers within the reaction vessels
• CPC Class Codes: B01J 2219/00484 by shaking, vibrating or oscillating of the reaction vessels
• CPC Class Codes: B01J 2219/00495 Means for heating or cooling the reaction vessels
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/00599 Solution-phase processes
• CPC Class Codes: B01J 2219/00691 using robots
• CPC Class Codes: B01J 2219/00743 Cells
• CPC Class Codes: B01L 2300/0681 Filter
• CPC Class Codes: B01L 2300/0816 Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2300/0867 Multiple inlets and one sample wells, e.g. mixing, dilution
• CPC Class Codes: B01L 2300/0877 Flow chambers
• CPC Class Codes: B01L 2300/10 Means to control humidity and/or other gases
• CPC Class Codes: B01L 2400/0466 Evaporation to induce underpressure
• CPC Class Codes: B01L 2400/0487 fluid pressure, pneumatics
• CPC Class Codes: B01L 3/5027 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 B01L3/5023 takes precedence; micromixers B01F33/30; microreactors for synthesis B01J19/0093; microcapillary devices in general B81B1/00
• CPC Class Codes: B01L 3/502715 : characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
• CPC Class Codes: B01L 3/502723 : characterised by venting arrangements
• CPC Class Codes: B01L 9/527 : for microfluidic devices, e.g. used for lab-on-a-chip
• CPC Class Codes: C12M 1/12 : with sterilisation, filtration or dialysis means
• CPC Class Codes: C12M 23/16 : Microfluidic devices; Capillary tubes integrated microfluidic structures B01L3/5027; microreactors B01J19/0093
• CPC Class Codes: C12M 35/08 : Chemical, biochemical or biological means, e.g. plasma jet, co-culture
• CPC Class Codes: C12M 41/48 : Automatic or computerized control automatic analysis G01N35/00
• CPC Class Codes: G01N 2035/00326 : Analysers with modular structure
• CPC Class Codes: Y10S 435/808 : Optical sensing apparatus
• CPC Class Codes: Y10S 435/809 : Incubators or racks or holders for culture plates or containers

Abstract

The present invention provides a variety of microscale bioreactors (microfermentors) and microscale bioreactor arrays for use in culturing cells. The microfermentors include a vessel for culturing cells and means for providing oxygen to the interior of the vessel at a concentration sufficient to support cell growth, e.g., growth of bacterial cells. Depending on the embodiment, the microfermentor vessel may have various interior volumes less than approximately 1 ml. The microfermentors may include an aeration membrane and optionally a variety of sensing devices. The invention further provides a chamber to contain the microfermentors and microfermentor arrays and to provide environmental control. Certain of the microfermentors include a second chamber that may be used, e.g., to provide oxygen, nutrients, pH control, etc., to the culture vessel and/or to remove metabolites, etc. Various methods of using the microfermentors, e.g., to select optimum cell strains or bioprocess parameters are provided. The invention provides microreactors having a variety of different designs, some of which incorporate active stirring and/or have the capability to operate in batch or fed-batch mode. The invention further provides an apparatus and methods for simultaneous operation of a plurality of microreactors, with monitoring of the individual microreactors during a run. The invention further provides methods of performing gene expression analysis on cells cultured in microreactors.

Claims

1. An apparatus for parallel operation of a plurality of microreactors comprising:

a chamber equipped with at least one element that supports or secures a microreactor tray inside the chamber, wherein the microreactor tray holds a plurality of microreactors;

a supporting component that holds a signal transmission device, wherein the supporting component and microreactor tray are controllably movable with respect to one another;

a plurality of support structures that contain or support an actuating device, wherein the support structures are movable with respect to the microreactor tray and wherein movement of the supporting component brings the supporting component into contact with a support structure, thereby moving the support structure so as to allow the supporting component to position a sensing device held by the supporting component into operably close proximity to microreactors mounted in or on a microreactor tray installed in the chamber; and

at least one spring that extends from the support structure to a wall of the chamber, and wherein movement of the support structure resulting from contact with the supporting component compresses the at least one spring.

2. The apparatus of claim 1, wherein termination of contact between the support structure and the supporting component releases compression of the at least one spring, thereby resulting in movement of the supporting structure to its previous position.