# US 10,870,825 B2 · Pulsatile perfusion bioreactor for mimicking, controlling, and optimizing blood vessel mechanics

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- Number: US 10,870,825 B2
- Document ID: US10870825B2
- Status: Granted
- Kind: B2
- Application number: 16/794,603
- Filed: 2020-02-19
- Published: 2020-06-11
- Granted: 2020-12-22
- Earliest claimed: 2015-04-07
- Assignees: University of South Carolina
- Applicants: University of South Carolina
- Inventors: John F. Eberth; Tarek Shazly; Boran Zhou; David A. Prim; Conrad Michael Gore
- Web page: https://patentgrep.com/patent/US10870825B2

## CPC

- C12M 29/12: {Pulsatile flow}
- C12M 21/08: {for producing artificial tissue or for ex-vivo cultivation of tissue (prostheses A61F2/00, grafts A61L27/00)}
- C12M 25/10: {Hollow fibers or tubes (hollow fiber modules in general B01D63/02)}
- C12M 29/00: {Means for introduction, extraction or recirculation of materials, e.g. pumps (pumps per se F04B)}
- C12M 29/10: {Perfusion}
- C12M 35/04: {Mechanical means, e.g. sonic waves, stretching forces, pressure or shear stimuli}
- C12M 41/40: {of pressure}
- C12N 5/0691: {Vascular smooth muscle cells; 3D culture thereof, e.g. models of blood vessels}
- 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}
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

A pulsatile perfusion bioreactor for culturing one or more engineered blood vessels having a lumen and a wall is provided. The bioreactor includes a chamber for holding the engineered blood vessel and cell culture media; a mechanical property monitoring system for measuring axial tensile stress and strain, circumferential tensile stress and strain, and/or shear stress imparted on the vessel wall; and a pump system for delivering cell culture media through the vessel lumen, wherein the vessel is exposed to a composite pressure waveform and a composite flow waveform as the media is delivered there through. The pump system includes a steady flow and peristaltic pumps. Further, the composite pressure and flow waveforms each include a mean component, a fundamental frequency component, and a second harmonic frequency component. The bioreactor also includes a computer interface for monitoring and adjusting the composite waveforms to maintain a predetermined stress level.

## Claims

### Claim 1

A method of culturing an engineered blood vessels having a lumen and a wall inside a pulsatile perfusion bioreactor, the method comprising:
inserting the engineered blood vessel to be cultured into a chamber;
filling the chamber with cell culture media;
delivering cell culture media through the lumen of the engineered blood vessel via a pump system, wherein the engineered blood vessel is exposed to a composite pressure waveform and a composite flow waveform as the cell culture media is delivered through the lumen, the pump system comprising a steady flow pump and a peristaltic pump, wherein the composite pressure waveform comprises a mean pressure component, a first harmonic frequency pressure component, and a second harmonic frequency pressure component, and wherein the composite flow waveform component comprises a mean flow component, a first harmonic frequency flow component, and a second harmonic frequency flow component;
measuring axial tensile stress, circumferential tensile stress, shear stress, axial stretch, circumferential stretch, or a combination thereof imparted on the wall of the engineered blood vessel via a mechanical property monitoring system;
monitoring and adjusting the composite pressure waveform, the composite flow waveform, or a combination thereof to maintain a predetermined axial tensile stress level, a predetermined circumferential stress level, a predetermined shear stress level, a predetermined axial stretch level, a predetermined circumferential stretch level, or a combination thereof via a computer interface.

### Claim 2 (depends on 1)

The method as in claim 1, wherein the composite pressure waveform and the composite flow waveform are derived from a pressure waveform and a flow waveform of a native blood vessel, wherein the engineered blood vessel is a replacement for the native blood vessel.

### Claim 3 (depends on 2)

The method as in claim 2, wherein the pulsatile perfusion bioreactor includes a compliance chamber, wherein the compliance chamber facilitates adjustment of the composite pressure waveform.

### Claim 4 (depends on 2)

The method as in claim 2, wherein pressure is measured via a pressure transducer and a stepper motor controlled pinch valve is utilized to adjust resistance within the pulsatile perfusion bioreactor, wherein adjusting the resistance results in an adjustment to the pressure.

### Claim 5 (depends on 1)

The method as in claim 1, wherein the steady flow pump delivers the mean pressure component of the composite pressure waveform and the mean flow component of the composite flow waveform.

### Claim 6 (depends on 1)

The method as in claim 1, wherein the peristaltic pump delivers a pulsatile flow of cell culture media through the lumen, wherein the peristaltic pump comprises a first pump head and a second pump head, wherein the first pump head provides the first harmonic frequency pressure component of the composite pressure waveform and the first harmonic frequency flow component of the composite flow waveform, and wherein the second pump head provides the second harmonic frequency pressure component of the composite pressure waveform and the second harmonic frequency flow component of the composite flow waveform.

### Claim 7 (depends on 6)

The method as in claim 6, wherein the peristaltic pump further comprises a third pump head, wherein the third pump head provides a third harmonic frequency pressure component of the composite pressure waveform and a third harmonic frequency flow component of the composite flow waveform.