# US 11,298,441 B2 · Biodegradable biomimetics of growth plate cartilage for the treatment of physeal injuries

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- Number: US 11,298,441 B2
- Document ID: US11298441B2
- Status: Granted
- Kind: B2
- Application number: 16/762,835
- Filed: 2018-11-06
- Published: 2020-08-20
- Granted: 2022-04-12
- Earliest claimed: 2017-11-08
- Assignees: The Regents of the University of Colorado, a body corporate
- Applicants: The Regents of the University of Colorado, A Body Corporate
- Inventors: Karin A. Payne; Stephanie Bryant; Virginia Ferguson; Nancy Hadley-Miller; Robert McLeod
- Web page: https://patentgrep.com/patent/US11298441B2

## CPC

- A61K 35/28: Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
- A61L 27/52: Hydrogels or hydrocolloids
- A61K 38/1841: {Transforming growth factor [TGF]}
- A61K 38/4886: {Metalloendopeptidases (3.4.24), e.g. collagenase}
- A61L 27/3834: {Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem cells}
- A61L 27/48: with macromolecular fillers
- A61L 27/54: Biologically active materials, e.g. therapeutic substances {(A61L27/227 takes precedence)}
- A61L 27/58: Materials at least partially resorbable by the body
- C12M 23/04: {Flat or tray type, drawers (C12M23/10, C12M23/12, C12M23/16 take precedence)}
- A61L 2300/236: Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
- A61L 2300/25: Peptides having up to 20 amino acids in a defined sequence
- A61L 2300/412: Tissue-regenerating or healing or proliferative agents
- A61L 2300/414: Growth factors
- A61L 2300/416: Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
- A61L 2430/06: for cartilage reconstruction, e.g. meniscus
- B33Y 80/00: Products made by additive manufacturing
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- 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)
- 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}
- 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

## Abstract

The present invention relates to the unexpected discovery of 3D printed biomimetics of growth plate cartilage and methods using the same for the treatment of growth plate defects. In certain embodiments, the methods prevent the growth of bony bars at the site of growth plate injury, thereby preventing growth arrest and/or deformity.

## Claims

### Claim 1

A biomimetic cartilage construct comprising a 3D printed structure in-filled with a cartilage mimetic hydrogel, wherein:
the 3D printed structure comprises an array of support pillars and at least two connecting lattice structures located at the top and base;
the 3D printed structure is printed into a three-dimensional shape having at least about 75% of the volume of the shape configured as open area available for in-filling with the cartilage mimetic hydrogel, wherein the three-dimensional shape is configured to provide structural support against longitudinal compressive forces and to provide lateral support against transverse movement during use;
the 3D printed structure being formed from at least one photopolymerizable material, the photopolymerizable material comprising at least one oligomeric or monomer material functionalized with at least one functionality selected from the group consisting of acrylate, methacrylate, thiol and norbornene; and
the cartilage mimetic hydrogel being formed from at least one multifunctional monomer and at least one degradable cross-linker.

### Claim 2 (depends on 1)

The construct of claim 1, wherein the 3D printed structure is printed into a pattern or shape selected from the group consisting of a honeycomb, grid, and mesh.

### Claim 3 (depends on 1)

The construct of claim 1, wherein the 3D printed structure comprises at least one biodegradable material.

### Claim 4 (depends on 1)

The construct of claim 1, wherein the at least one multifunctional monomer comprises at least one material selected from the group consisting of poly(ethylene glycol), poly(ethylene glycol) diacrylate, poly(ethylene glycol) methacrylate, acryloyl-PEG-RGD, norbornene functionalized PEG.

### Claim 5 (depends on 1)

The construct of claim 1, wherein the at least one degradable cross-linker is an enzyme degradable peptide.

### Claim 6 (depends on 5)

The construct of claim 5, wherein the enzyme degradable peptide is a peptide that can be degraded by at least one matrix metalloproteinase.

### Claim 7 (depends on 5)

The construct of claim 5, wherein the enzyme degradable peptide is selected from the group consisting of GCVPLSLYSGCG (SEQ ID NO: 13), CVPLSLYSGC (SEQ ID NO: 14) and CRGDS (SEQ ID NO: 15).

### Claim 8 (depends on 1)

The construct of claim 1, wherein the cartilage mimetic hydrogel comprises at least one biomimetic moiety selected from the group consisting of chondroitin sulfate, thiolated chondroitin sulfate, methacrylated chondroitin sulfate, and cell adhesion peptide RGD.

### Claim 9 (depends on 1)

The construct of claim 1, wherein the cartilage mimetic hydrogel comprises at least one biological factor selected from the group consisting of SDF-1α, CCL25, TGF-β1, TGF-β3, ranibizumab, bevacizumab, lapatinib, sunitinib, sorafenib, axitinib, and pazopanib.

### Claim 10 (depends on 9)

The construct of claim 9, wherein at least a portion of the at least one biological factor is covalently bound to the cartilage mimetic hydrogel.

### Claim 11 (depends on 1)

The construct of claim 1, further comprising mesenchymal stem cells.

### Claim 12 (depends on 1)

A method of treating a cartilage injury in a subject, the method comprising placing the construct of claim 1 in a void at the site of the cartilage injury.

### Claim 13 (depends on 12)

The method of claim 12, wherein, the cartilage injury is a growth plate injury.

### Claim 14 (depends on 13)

The method of claim 13, wherein, before the placing step, a bony bar is first surgically removed from the growth plate injury in the subject, thus generating, at least in part, the void.

### Claim 15 (depends on 13)

The method of claim 13, wherein, before the placing step, damaged growth plate cartilage is first surgically removed from the site of the growth plate injury, thus generating, at least in part, the void.

### Claim 16 (depends on 13)

The method of claim 13, which minimizes, reverses, or ameliorates at least one of the following:
growth of bony bars in cartilage tissue at the site of growth plate injury;
arrest of bone growth at the site of growth plate injury; and
bone deformities at the site of growth plate injury.

### Claim 17 (depends on 13)

The method of claim 13, wherein the subject is an infant, toddler, child, juvenile, adolescent, or young adult.

### Claim 18 (depends on 12)

The method of claim 12, wherein the subject is a mammal.

### Claim 19 (depends on 17)

The method of claim 17, wherein the subject is a human.

### Claim 20 (depends on 1)

The construct of claim 1, wherein the 3D printed structure comprises an array of support pillars and a connecting lattice structure located at least at the base, middle and top.

### Claim 21 (depends on 20)

The construct of claim 20, wherein the array of support pillars is configured to provide structural support against longitudinal compressive forces and the connecting lattice structure is configured to provide lateral support against transverse movement during use.