# US 10,119,622 B2 · Organ on chip integration and applications of the same

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- Number: US 10,119,622 B2
- Document ID: US10119622B2
- Status: Granted
- Kind: B2
- Application number: 15/826,007
- Filed: 2017-11-29
- Published: 2018-03-22
- Granted: 2018-11-06
- Earliest claimed: 2017-11-29
- Assignees: Vanderbilt University
- Applicants: Vanderbilt University
- Inventors: Frank E. Block, III; Philip C. Samson; Erik M. Werner; Dmitry A. Markov; Ronald S. Reiserer; Jennifer R. Mckenzie; David E. Cliffel; William J. Matloff; Frank E. Block, Jr.; Joseph R. Scherrer; W. Hunter Tidwell; John P. Wikswo
- Web page: https://patentgrep.com/patent/US10119622B2

## CPC

- F16K 11/163: {only turns}
- B01L 3/502715: {characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces}
- B01L 3/50273: {characterised by the means or forces applied to move the fluids}
- B01L 3/502738: {characterised by integrated valves (throttle valves in microfluidic sample containers B01L3/502746)}
- C12M 21/08: {for producing artificial tissue or for ex-vivo cultivation of tissue (prostheses A61F2/00, grafts A61L27/00)}
- C12M 23/16: {Microfluidic devices; Capillary tubes (integrated microfluidic structures B01L3/5027; microreactors B01J19/0093)}
- C12M 23/44: {Multiple separable units; Modules}
- C12M 23/52: {Mobile; Means for transporting the apparatus (transportable laboratories B01L1/52)}
- C12M 29/00: {Means for introduction, extraction or recirculation of materials, e.g. pumps (pumps per se F04B)}
- C12M 29/02: {Percolation}
- C12M 29/10: {Perfusion}
- C12M 29/20: {Degassing; Venting; Bubble traps (means for collection or storage of gas C12M23/36; gas collection apparatus for laboratory use B01L5/02)}
- F04B 19/006: {Micropumps (F04B43/043 and F04B43/095 take precedence)}
- F04B 43/12: having peristaltic action
- F04B 43/1269: {the rotary axes of the rollers lying in a plane perpendicular to the rotary axis of the driving motor}
- F04B 43/1292: {Pumps specially adapted for several tubular flexible members}
- F16K 99/0023: {with ball-shaped valve members}
- B01L 2200/028: Modular arrangements
- B01L 2200/0684: Venting, avoiding backpressure, avoid gas bubbles
- B01L 2200/10: Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
- B01L 2200/18: Transport of container or devices
- B01L 2300/0816: Cards, e.g. flat sample carriers usually with flow in two horizontal directions
- B01L 2300/0819: Microarrays; Biochips
- B01L 2300/0867: Multiple inlets and one sample wells, e.g. mixing, dilution
- B01L 2300/0874: Three dimensional network
- B01L 2300/123: Flexible; Elastomeric
- B01L 2400/0481: squeezing of channels or chambers
- B01L 2400/0487: fluid pressure, pneumatics
- B01L 2400/0644: rotary valves
- B01L 2400/0655: pinch valves
- F16K: VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING {(devices for emptying and evacuating the excess liquid in valves or conduits F16L55/07)}
- B01L: CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- 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}
- F04B: POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS (machines for liquids, or pumps, of rotary-piston or oscillating-piston type F04C; non-positive-displacement pumps F04D; pumping of fluid by direct contact of another fluid or by using inertia of fluid to be pumped F04F)

## Abstract

A rotary planar peristaltic micropump (RPPM) includes an actuator having a shaft engaged with a motor such that activation of the motor causes the shaft to rotate, and a bearing assembly engaged with the shaft. The bearing assembly has a bearing cage defining a plurality of spaced-apart openings thereon, and a plurality of rolling-members accommodated in the plurality of spaced-apart openings of the bearing cage, such that when the shaft rotates, the plurality of rolling-members of the bearing assembly rolls along a circular path. The RPPM also includes a fluidic path in fluidic communication with first and second ports. The fluidic path is positioned under the actuator and coincident with the circular path, such that when the shaft of the actuator rotates, the plurality of rolling-members of the bearing assembly rolls along the fluidic path to cause a fluid to transfer between the first and second ports.

## Claims

### Claim 1

A rotary planar peristaltic micropump (RPPM), comprising:
(a) an actuator, comprising:
a shaft engaged with a motor such that activation of the motor causes the shaft to rotate; and
a bearing assembly engaged with the shaft, wherein the bearing assembly comprises a bearing cage defining a plurality of spaced-apart openings thereon, and a plurality of rolling-members accommodated in the plurality of spaced-apart openings of the bearing cage, such that when the shaft rotates, the plurality of rolling-members of the bearing assembly rolls along a circular path; and
(b) a fluidic path in fluidic communication with a first port and a second port, wherein the fluidic path is positioned under the actuator and is coincident with the circular path, such that when the shaft of the actuator rotates, the plurality of rolling-members of the bearing assembly rolls along the fluidic path to cause a fluid to transfer between the first port and the second port,
wherein the bearing cage has a first cylindrical portion on which the plurality of spaced-apart openings is defined, and a second cylindrical portion extending coaxially from the first cylindrical portion, wherein the first cylindrical portion has a diameter that is greater than that of the second cylindrical portion, and wherein the second cylindrical portion defines a hole along its central axis into which the shaft is mounted,
wherein the bearing assembly further comprises:
a thrust bearing positioned between the motor and the second cylindrical portion of the bearing cage;
an alignment bearing positioned against the first cylindrical portion of the bearing cage; and
a tensioning spring positioned between the thrust bearing and the alignment bearing.

### Claim 2 (depends on 1)

The RPPM of claim 1, wherein each of the plurality of rolling-members comprises a ball, a roller, or a wheel.

### Claim 3

A rotary planar peristaltic micropump (RPPM), comprising:
(a) an actuator, comprising:
a shaft engaged with a motor such that activation of the motor causes the shaft to rotate; and
a bearing assembly engaged with the shaft, wherein the bearing assembly comprises a bearing cage defining a plurality of spaced-apart openings thereon, and a plurality of rolling-members accommodated in the plurality of spaced-apart openings of the bearing cage, such that when the shaft rotates, the plurality of rolling-members of the bearing assembly rolls along a circular path;
(b) a fluidic path in fluidic communication with a first port and a second port, wherein the fluidic path is positioned under the actuator and is coincident with the circular path, such that when the shaft of the actuator rotates, the plurality of rolling-members of the bearing assembly rolls along the fluidic path to cause a fluid to transfer between the first port and the second port;
(c) a substrate have a first surface and a second surface;
(d) an elastomer member positioned between the bearing cage and the first surface of the substrate;
(e) motor alignment/attachment pins vertically positioned on the first surface of the substrate such that the actuator is located between the motor alignment/attachment pins,
wherein the fluidic path is formed on the first surface of the substrate by a hot-embossing, or an injection-molding, or an etching process, or in an elastomer member.

### Claim 4 (depends on 3)

The RPPM of claim 3, wherein the bearing assembly further comprises:
(a) a driving pin; and
(b) an interface collar for providing the attachment of the driving pin to the shaft.

### Claim 5 (depends on 4)

The RPPM of claim 4, wherein the bearing assembly further comprises:
(a) a washer positioned between the shaft and the bearing cage; and
(b) a second elastomer sheet positioned between the washer and the bearing cage.

### Claim 6 (depends on 5)

The RPPM of claim 5, wherein the bearing assembly further comprises an auto-centering needle bearing positioned at an edge of the bearing cage.

### Claim 7 (depends on 4)

The RPPM of claim 4, wherein the bearing assembly further comprises:
(a) a pressed fit washer positioned on the bearing cage;
(b) a pressure transfer bearing positioned on the pressed fit washer;
(c) a tension holding plate positioned on the pressure transfer bearing and adjustably mounted to the motor alignment/attachment pins for transferring tensioning pressure via the pressure transfer bearing to fluidic paths thereunder; and
(d) centering pins positioned against the edge of the bearing cage.

### Claim 8

A rotary planar valve (RPV), comprising
(a) an actuator, comprising:
a shaft engaged with a motor such that activation of the motor causes the shaft to rotate; and
a bearing assembly engaged with the shaft, wherein the bearing assembly comprises a bearing cage defining a plurality of spaced-apart openings thereon, and a plurality of rolling-members accommodated in the plurality of spaced-apart openings of the bearing cage, wherein the number of the plurality of rolling-members is less than that of the plurality of spaced-apart openings of the bearing cage such that the bearing assembly has at least one no-rolling-member opening that accommodates a no-rolling-member; and
(b) a plurality of selectively controllable fluidic paths coupled to each other, positioned under the actuator in relation to the plurality of equally spaced-apart openings of the bearing cage such that at least one selectively controllable fluidic path is positioned under the at least one no-rolling-member opening so that a fluid flow is allowed through the at least one selectively controllable fluidic path, while the other selectively controllable fluidic paths are respectively positioned under the openings having the rolling-members so that no fluid flows are allowed through the other selectively controllable fluidic paths.

### Claim 9 (depends on 8)

The RPV of claim 8, wherein each of the plurality of rolling-members comprises a ball, a roller, or a wheel.

### Claim 10 (depends on 8)

The RPV of claim 8, wherein the plurality of spaced-apart openings of the bearing cage is spaced-equally defined on the bearing cage, wherein each two adjacent openings through the center of the bearing cage define an angle θ=2π/K, K being the number of the plurality of equally spaced-apart openings.

### Claim 11 (depends on 10)

The RPV of claim 10, wherein when the shaft of the actuator rotates a desired angle of (k×θ), k being 1, 2, . . . K, the at least one no-rolling-member opening is selectively placed over a desired one of the selectively controllable fluidic paths.

### Claim 12 (depends on 10)

The RPV of claim 10, further comprising at least one always-open fluidic path coupled to the plurality of selectively controllable fluidic paths, positioned under the actuator in offset from the plurality of equally spaced-apart openings, such that the at least one offset fluidic path is in fluid communication with the at least one selectively controllable fluidic path under the at least one no-rolling-member opening, and the other selectively controllable fluidic paths under the openings having the rolling-members are closed.

### Claim 13

An integrated MicroFormulator, comprising:
(a) a plurality of inlets for providing a plurality of solutions;
(b) a plurality of outlets;
(c) a plurality of fluidic switches in fluid communication with the plurality of inlets and the plurality of outlets;
(d) one or more on-chip pumps in fluid communication with the plurality of fluidic switches;
(e) a microfluidic chip having a mixer region and a plurality of fluid connections in fluid communication with the at least one pump, the plurality of valves, the plurality of inlets and the plurality of outlets; and
(f) a power and control unit programmed to selectively and individually control the one or more on-chip pumps and the plurality of fluidic switches for providing a desired substance that is a mixture of selected solutions from the plurality of solutions for cultivation, maintenance, and/or analysis of a bio-object, wherein the integrated MicroFormulator operably has a Load Sample mode, a Sample to Mixer mode, a Mix mode, and a Sample Output mode,
wherein the one or more on-chip pumps comprise a rotary planar peristaltic micropump (RPPM), wherein each of the plurality of fluidic switches comprises a rotary planar valve (RPV), and wherein each RPV comprises a normally closed (NC) rotary planar valve.

### Claim 14 (depends on 13)

The integrated MicroFormulator of claim 13, wherein the power and control unit comprises a microcontroller, and a power supply.

### Claim 15 (depends on 14)

The integrated MicroFormulator of claim 14, wherein the microcontroller is provided with at least one of a wireless communication protocol and a wired communication protocol.

### Claim 16 (depends on 14)

The integrated MicroFormulator of claim 14, wherein the RPPM and each RPV are driven by a respective motor that is controlled by the microcontroller.

### Claim 17

An integrated MicroFormulator, comprising:
(a) a plurality of inlets for providing a plurality of solutions;
(b) a plurality of outlets;
(c) a plurality of fluidic switches in fluid communication with the plurality of inlets and the plurality of outlets;
(d) one or more on-chip pumps in fluid communication with the plurality of fluidic switches;
(e) a microfluidic chip having a mixer region and a plurality of fluid connections in fluid communication with the at least one pump, the plurality of valves, the plurality of inlets and the plurality of outlets; and
(f) a power and control unit programmed to selectively and individually control the one or more on-chip pumps and the plurality of fluidic switches for providing a desired substance that is a mixture of selected solutions from the plurality of solutions for cultivation, maintenance, and/or analysis of a bio-object, wherein the integrated MicroFormulator operably has a Load Sample mode, a Sample to Mixer mode, a Mix mode, and a Sample Output mode,
wherein the one or more on-chip pumps comprise a rotary planar peristaltic micropump (RPPM), wherein each of the plurality of fluidic switches comprises a rotary planar valve (RPV)
wherein the plurality of fluidic switches comprises:
an input RPV fluidically connected to the plurality of inlets;
a first RPV having five ports fluidically connected to the input RPV, the mixer region, and the RPPM, a sample output port of the outlets, and a first waste port of the outlets, respectively; and
a second RPV having three ports fluidically connected to the mixer region, the RPPM, and a second waste port of the outlets, respectively.

### Claim 18

An integrated MicroFormulator, comprising:
(a) a plurality of inlets for providing a plurality of solutions;
(b) a plurality of outlets;
(c) a plurality of fluidic switches in fluid communication with the plurality of inlets and the plurality of outlets;
(d) one or more on-chip pumps in fluid communication with the plurality of fluidic switches;
(e) a microfluidic chip having a mixer region and a plurality of fluid connections in fluid communication with the at least one pump, the plurality of valves, the plurality of inlets and the plurality of outlets; and
(f) a power and control unit programmed to selectively and individually control the one or more on-chip pumps and the plurality of fluidic switches for providing a desired substance that is a mixture of selected solutions from the plurality of solutions for cultivation, maintenance, and/or analysis of a bio-object, wherein the integrated MicroFormulator operably has a Load Sample mode, a Sample to Mixer mode, a Mix mode, and a Sample Output mode,
wherein the one or more on-chip pumps comprise a rotary planar peristaltic micropump (RPPM), wherein each of the plurality of fluidic switches comprises a rotary planar valve (RPV)
wherein the microfluidic chip further has a shuttle region.

### Claim 19 (depends on 18)

The integrated MicroFormulator of claim 18, wherein the plurality of fluidic switches comprises:
(a) an input RPV fluidically connected to the shuttle region, and stock solution ports of the inlets;
(b) a first RPV having five ports fluidically connected to the mixer region, the RPPM, an input buffer port of the inlets, a sample output port of the outlets, and a first waste port of the outlets, respectively; and
(c) a second RPV having four ports fluidically connected to the mixer region, the RPPM, the shuttle region and a second waste port of the outlets, respectively.

### Claim 20 (depends on 18)

The integrated MicroFormulator of claim 18, wherein the plurality of fluidic switches comprises:
(a) an input RPV fluidically connected to the shuttle region, and stock solution ports of the inlets; and
(b) an operation mode selector valve fluidically connected to the input RPV, the shuttle region, the mixer region, the RPPM, a sample output port of the outlets, and a waste port of the outlets; and
wherein the RPPM is fluidically connected to the mixer.

### Claim 21

A method for cultivation, maintenance, and/or analysis of one or more bio-objects, each bio-object including an organ, a tissue construct, or a group of cells, comprising:
(a) providing a platform having one or more integrated bio-object microfluidics modules fluidically interconnected to each other, each integrated bio-object microfluidics module comprising:
i. one or more on-chip pumps;
ii. a plurality of fluidic switches; and
iii. a microfluidic chip in fluid communication with the one or more on-chip pumps and the plurality of fluidic switches, comprising at least one chamber for accommodating the bio-object and a plurality of fluidic paths connecting the chamber, the one or more on-chip pumps and the plurality of fluidic switches; and
(b) selectively and individually controlling the one or more on-chip pumps and the plurality of fluidic switches of each integrated bio-object microfluidics module to perform bio-object microfluidics functions for cultivation, maintenance, and/or analysis of the respective bio-object, wherein the bio-object microfluidics functions comprise perfusion of the respective bio-object, analysis of metabolic activities of the respective bio-object, and formulation of custom media to support the respective bio-object and guide stem cell differentiation.

### Claim 22 (depends on 21)

The method of claim 21, further comprising selectively removing one integrated bio-object microfluidics module from the platform.

### Claim 23 (depends on 22)

The method of claim 22, further comprising replacing the removed integrated bio-object microfluidics module with a desired integrated bio-object microfluidics module.

### Claim 24 (depends on 21)

The method of claim 21, further comprising transporting the platform from one location to another location.