Interconnections of multiple perfused engineered tissue constructs and microbioreactors, multi-microformulators and applications of the same

• US 10,023,832 B2
• Filed: 06/23/2016
• Issued: 07/17/2018
• Est. Priority Date: 07/16/2013
• Status: Active Grant

• Current Assignee: Vanderbilt University
• Original Assignee: Vanderbilt University
• Inventors: Wikswo, John P., Markov, Dmitry A., Samson, Philip C., Block, III, Frank E., Schaffer, David K., Reiserer, Ronald S.
• Primary Examiner(s): Hansen, Kenneth J
• Application Number:
  US15/191,092
• Publication Number:
  US 20170081625A1
• Time in Patent Office: 754 Days
• Field of Search: 422502-505, 422509, 422510, 422537-539
• CPC Class Codes: A01N 1/0247 for perfusion, i.e. for circulating fluid through organs, blood vessels or other living parts
• 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: C12M 23/12 Well or multiwell plates C12M25/04 takes precedence
• CPC Class Codes: C12M 23/16 Microfluidic devices; Capillary tubes integrated microfluidic structures B01L3/5027; microreactors B01J19/0093
• CPC Class Codes: C12M 23/44 Multiple separable units; Modules
• CPC Class Codes: C12M 23/58 Reaction vessels connected in series or in parallel combinations of bioreactors with other apparatus, C12M43/00
• CPC Class Codes: C12M 29/00 Means for introduction, extraction or recirculation of materials, e.g. pumps pumps per se F04B
• CPC Class Codes: C12M 41/48 Automatic or computerized control automatic analysis G01N35/00
• CPC Class Codes: F04B 43/0045 with a number of independent working chambers which are actuated successively by one mechanism

Abstract

The invention relates to a system of fluidic valves and pumps and associated fluidic channels integratable into a bio-object microfluidics module. The module includes input and output buses; upstream and downstream interconnection bus control valves (CVs) coupled to the input and output buses, respectively. It may include arterial, venous, wash and waste bus lines, each connecting between the upstream and downstream interconnection bus CVs. It may also include an input CV connecting to the arterial bus line, upstream interconnection bus CV, bio-object and inlets, and an output CV connecting to the bio-object, input CV, downstream interconnection bus CV and outlets; and a pump connecting between the input CV and bio-object. The system can be arranged to provide MicroFormulator functionality enabling precise mixtures of drugs, chemicals, or biochemicals to be delivered in a time-dependent fashion to biological entities housed in individual wells or chambers.

Claims

1. A microfluidics module molded from elastomeric material, comprising:

a fluidic circuit having a plurality of channels, chambers, vials, wells and fluid ports formed such that when at least one selector valve and at least one pump are placed on the fluidic circuit, the fluidic circuit together with the at least one selector valve and the at least one pump operably construe at least one MicroFormulator for individually controlling a concentration of fluidic media in each well of the plurality of wells with time-division multiplexing through a sequence of selecting a plurality of reservoirs by the at least one selector valve and pump speed and duration actuations of the at least one pump, wherein each of the at least one selector valve comprises a multiport, rotary planar valve (RPV), each of the at least one pump comprises a rotary planar peristaltic micropump (RPPM), and each of the RPV and the RPPM comprises a rotary actuator, configured such that when the rotary actuator of the RPV activates, the RPV allows a fluidic medium from the selected reservoir to pass through, and when the rotary actuator of the RPPM activates, the RPPM withdraws the fluidic medium from the selected reservoir and delivers it to one of the wells.

2. The microfluidics module of claim 1, further comprising multiple flat layers bonded sequentially or simultaneously to define all or part of the fluidic circuit.

3. A fluidic system for long-term control of a concentration of within each of a well plate that is maintained in an incubator, comprising:

at least one MicroFormulator, each of the at least one MicroFormulator comprising;

a plurality of reservoirs;

at least one selector valve fluidically coupled to the plurality of reservoirs to select at least one reservoir; and

at least one pump fluidically coupled to the at least one selector valve to withdraw fluid from the selected reservoir and deliver it to at least one output tube, wherein the at least one output tube is connectable to at least one well of a plurality of wells of the well plate,

wherein each of the at least one selector valve comprises a multiport, rotary planar valve (RPV), each of the at least one pump comprises a rotary planar peristaltic micropump (RPPM), and each of the RPV and the RPPM comprises a rotary actuator, configured such that when the rotary actuator of the RPV activates, the RPV allows a fluidic medium from the selected reservoir to pass through, and when the rotary actuator of the RPPM activates, the RPPM withdraws the fluidic medium from the selected reservoir and delivers it to the well of the well plate through the at least one output tube at a rate and a volume, whereby a concentration of fluidic media in the well with the fluid output from the at least one output tube is controllable with time-division multiplexing.

4. The fluidic system of claim 3, wherein the multiport, rotary planar valve comprises a missing-ball, normally open rotary planar valve (NO-RPV), or a fixed-ball, rotating-actuator, normally closed rotary planar valve (NC-RPV).

5. The fluidic system of claim 3, wherein the at least one selector valve is configured to select different reservoirs at different periods of time.

6. The fluidic system of claim 5, wherein the at least one pump is driven such that the fluid of the selected reservoir outputs from the at least one output tube at a predetermined flow rate.

7. The fluidic system of claim 6, wherein the predetermined flow rate varies with time.

8. The fluidic system of claim 3, wherein the at least one selector valve comprises a first selector valve fluidically coupled to the plurality of reservoirs to select at least one reservoir, and a second selector valve fluidically coupled to the at least one pump for directing the fluid of the selected reservoir output from the at least one pump to one of the at least one of the output tubes, wherein each output tube in turn is connectable to each well of the plurality of wells of the well plate.

9. The fluidic system of claim 8, wherein the at least one MicroFormulator comprises a first MicroFormulator and a second MicroFormulator, configured such that the first MicroFormulator delivers the fluid of the selected reservoir individually to each well of the plurality of wells of the well plate and a second MicroFormulator independently removes the fluid from each well of the well plate simultaneously or sequentially.

10. The fluidic system of claim 3, wherein through a sequence of selecting the at least one reservoir of the plurality of reservoirs by the at least one selector valve and pump speed and duration actuations of the at least one pump, a time-dependent sequence for metered delivery of aliquots of drugs, chemicals, biochemicals, or fluid medias from a respective reservoir of the plurality of reservoirs is applicable to each well of the plurality of wells in coordination with time-dependent metered withdrawal of existing fluids therein such that a time-dependent biochemical concentration is operably created within each well of the plurality of wells for exposing cells to physiologically realistic or other time-dependent concentration profiles of one or more chemical or biochemical species.

11. The fluidic system of claim 9, wherein the at least one MicroFormulator comprises eight MicroFormulators, each MicroFormulator configured to individually address 12 wells of the well plate.

12. The fluidic system of claim 3, further comprising at least one splitter fluidically coupled to the at least one output tube and each well of the plurality of wells of the well plate for addressing each well of the plurality of wells with the fluid output from the at least one output tube.

13. The fluidic system of claim 3, further comprising a microcontroller for individually controlling the at least one selector valve and the at least one pump.

14. The fluidic system of claim 13, wherein the microcontroller is provided with a wireless communication protocol.