# US 11,439,731 B2 · Artificial tissue progenitor and method for preparing the same

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- Number: US 11,439,731 B2
- Document ID: US11439731B2
- Status: Granted
- Kind: B2
- Application number: 16/113,509
- Filed: 2018-08-27
- Published: 2019-02-07
- Granted: 2022-09-13
- Earliest claimed: 2016-09-14
- Assignees: Revotek Co., Ltd
- Applicants: Revotek Co., Ltd
- Inventors: Yujian James Kang; Xiao Zuo; Mingchun Du
- Web page: https://patentgrep.com/patent/US11439731B2

## CPC

- A61L 27/507: {for artificial blood vessels (apparatus for applying cells on a blood vessel prosthesis A61F2/062)}
- A61L 27/18: obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
- A61L 27/3625: {Vascular tissue, e.g. heart valves}
- A61L 27/3834: {Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem cells}
- B33Y 10/00: Processes of additive manufacturing
- B33Y 80/00: Products made by additive manufacturing
- C12M 21/08: {for producing artificial tissue or for ex-vivo cultivation of tissue (prostheses A61F2/00, grafts A61L27/00)}
- C12M 25/14: {Scaffolds; Matrices (in general C12N5/0068)}
- C12M 25/16: {Particles; Beads; Granular material; Encapsulation (chemical or physical processes conducted in the presence of fluids and solid particles B01J8/00)}
- C12M 33/00: {Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus (chemical or physical laboratory apparatus in general B01L, devices for taking cell samples A61B10/0045, withdrawing or distributing predetermined quantities of fluid B01L99/00)}
- C12N 5/0012: {Cell encapsulation}
- C12N 5/0068: {General culture methods using substrates (for specific animal cell type C12N5/06)}
- C12N 5/0667: {Adipose-derived stem cells [ADSC]; Adipose stromal stem cells}
- C12N 5/0691: {Vascular smooth muscle cells; 3D culture thereof, e.g. models of blood vessels}
- A61F 2210/0004: bioabsorbable
- A61F 2230/0063: Three-dimensional shapes
- C12N 2513/00: 3D culture
- C12N 2533/30: Synthetic polymers
- C12N 2533/54: Collagen; Gelatin
- C12N 2533/56: Fibrin; Thrombin
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- B33Y: ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
- 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)
- A61F: FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS (dental prosthetics A61C)

## Abstract

The invention relates to the technical filed of tissue engineering and 3D printing, particularly relates to an artificial tissue progenitor and a method for preparing the same. In particular, the invention relates to an artificial tissue progenitor comprising a solid support and a plurality of microcapsules, wherein at least one microcapsule is attached to the solid support, and the microcapsule comprises a cell and a biocompatible material encapsulating the cell, to a method for preparing the artificial tissue progenitor, to a kit and a package useful for preparing the artificial tissue progenitor, to an artificial tissue obtained by culturing the artificial tissue progenitor, such as an artificial lumen, to a lumen implant or a lumen model containing the artificial tissue progenitor or the artificial lumen, to use of the artificial tissue progenitor in the manufacture of an artificial tissue, a lumen implant or a lumen model, and to use of the artificial tissue in the manufacture of a lumen implant or lumen model.

## Claims

### Claim 1

An artificial tissue progenitor comprising a solid support and a plurality of microcapsules, wherein
each of the microcapsules comprises cells, a core and a shell, wherein the core encapsulates 25-5000 cells and the shell encloses the core, and wherein the core and the shell are independently made from a biodegradable polymeric material, wherein the biodegradable polymeric material for preparing the core is collagen, and the biodegradable polymeric material for preparing the shell is polylysine;
the cells are selected from the group consisting of adipose-derived mesenchymal stem cells, and bone marrow mesenchymal stem cells;
the artificial tissue progenitor is a tube, the solid support is a tubular solid support, the plurality of microcapsules forms one tubular biological construct, and the tubular biological construct has an outer wall attached to the inner wall of the tubular solid support by a medical adhesive; and
the artificial tissue progenitor is a blood vessel progenitor.

### Claim 2 (depends on 1)

The artificial tissue progenitor of claim 1, having one or more features selected from the following:
(1) the microcapsules each independently have a size of 100-2000 μm;
(2) the microcapsules are each independently spherical;
(3) the microcapsules are in a gel state;
(4) the cells are adipose-derived mesenchymal stem cells and;
(5) the cells are obtained from a human, a monkey, a pig or a dog.

### Claim 3 (depends on 1)

The artificial tissue progenitor of claim 1, having one or more features selected from the following:
(1) the artificial tissue progenitor has an inner diameter of 1 mm to 3 cm;
(2) the artificial tissue progenitor has a uniform thickness;
(3) the tubular solid support has a length of 1 cm to 40 cm; and
(4) the tubular solid support has an inner diameter of 1 mm to 3 cm.

### Claim 4 (depends on 1)

The artificial tissue progenitor of claim 1, wherein the medical adhesive is a tissue adhesive comprising octyl 2-cyanoacrylate.

### Claim 5 (depends on 1)

The artificial tissue progenitor of claim 1, wherein the medical adhesive comprises alpha-cyanoacrylate.

### Claim 6 (depends on 1)

A method of preparing the artificial tissue progenitor according to claim 1, wherein the artificial tissue progenitor is in a form of tube, wherein the method comprises the following steps:
(I) preparing the tubular biological construct; and
(II) attaching the tubular biological construct to the inner wall of the tubular solid support.

### Claim 7 (depends on 6)

The method of claim 6, wherein the tubular biological construct is prepared by a 3D bio-printer.

### Claim 8 (depends on 7)

The method of claim 7, wherein the 3D bio-printer comprises a first ink cartridge for providing a bio-ink, a second ink cartridge for providing the medical adhesive, a first printer head connected to the second ink cartridge, a second printer head connected to the second ink cartridge, and a rotary rod, wherein the outer wall of the rotary rod is covered with an elastic film.

### Claim 9 (depends on 6)

The method of claim 6, comprising the following steps:
(1) providing a bio-ink in a first ink cartridge of a 3D bio-printer, wherein the bio-ink comprises a carrier and one or more microcapsules, and providing the medical adhesive in a second ink cartridge of the 3D bio-printer;
(2) printing the bio-ink on a predetermined area of an elastic film which is covered on the out wall of a rotary rod of the 3D bio-printer via a first printer head connected to the first ink cartridge of the 3D bio-printer, and obtaining the tubular biological construct;
(3) printing the medical adhesive on the tubular biological construct obtained in step (2) via a second printer head connected to the second ink cartridge of the 3D bio-printer, and obtaining a medical adhesive layer;
(4) sheathing the tubular solid support on the outer surface of the tubular biological construct with the medical adhesive layer obtained in step (3);
(5) expanding the elastic film, thus attaching the tubular biological construct with the adhesive layer to the inner wall of the tubular solid support, immobilizing the biological construct with the solid support by the medical adhesive, and obtaining the artificial tissue progenitor;
optionally, the method further comprises separating the tubular biological construct from the elastic film.

### Claim 10 (depends on 1)

An artificial blood vessel or a vascular patch obtained by culturing the artificial tissue progenitor according to claim 1.

### Claim 11 (depends on 1)

A lumen implant comprising an artificial tissue progenitor according to claim 1 or an artificial blood vessel or a vascular patch obtained by culturing the artificial tissue progenitor according to claim 1.

### Claim 12 (depends on 11)

The lumen implant according to claim 11, having a linear tubular structure.

### Claim 13 (depends on 10)

A blood vessel model, comprising the artificial blood vessel according to claim 10 and having a linear tubular structure.

### Claim 14 (depends on 1)

The artificial tissue progenitor according to claim 1, wherein the cells are adipose-derived mesenchymal stem cells.