Medical implant

Patent metadata

Field	Value
Publication number	US-10765779-B2
Application number	US-201615747410-A
Country	US
Kind code	B2
Filing date	Jul 25, 2016
Priority date	Jul 24, 2015
Publication date	Sep 8, 2020
Grant date	Sep 8, 2020

Abstract

The present invention relates to a cell-free, multi-layered medical device having bespoke, multifunctional bioactivity for the purpose of regeneration of skeletal tissues. The medical device may actively promote homing of stem cells into the medical device and promote their differentiation into the required cell type and promote de-novo tissue formation. The invention includes methods of making the medical device, uses of the medical device in promoting regeneration of the articular cartilage of a joint surface and in promoting healing and regeneration of skeletal tissues, for example, meniscal cartilage, tendon and ligament tissues and also healing of bone tissue indications such as fractures.

First claim

The invention claimed is:

1. An acellular biomimetic medical device comprising a scaffold coated in or adsorbed on its surfaces with a first layer comprising a cationic agent, the first layer being covered or coated with a second layer comprising an anionic oligosaccharide or polysulphated moiety, which is non-covalently bound to a mixture of a plurality of bioactive factors, wherein the plurality of bioactive factors comprises:
(i) an agent that can stimulate stem cell differentiation and/or promote appropriate extracellular matrix formation for the tissue to be regenerated selected from the transforming growth factor β group; and
(ii) a stem cell homing or migratory factor which is a chemokines and optionally
(iii) an agent that inhibits enzymes associated with the breakdown or catabolism of extracellular matrix.

2. The device according to claim 1 , wherein the first and second layers are non-covalently bound together.

3. The device according to claim 1 , wherein the scaffold is synthetic, natural, and/or selected from the group comprising polyester compositions, polylactic acid, polylactic acid-glycolic acid copolymer compositions, polycaprolactone, polyester-polyallylamine copolymers, collagens, peptides, silks, chitosan, hyaluronan-based polymers, decellularized tissue, calcium phosphate-based materials, hydroxyapatite and ceramic based biomaterials and combinations and compositions of the foregoing scaffold materials with ceramic based biomaterials.

4. The device according to claim 1 , wherein the cationic agent is a stable unsaturated amine or is allylamine.

5. The device according to claim 1 , wherein the second layer comprises an anionic oligosaccharide or a sulphated moiety.

6. The device according to claim 5 , wherein the anionic oligosaccharide is selected from the group comprising heparin and heparan sulphate, dermatan sulphate, chondroitin-4-sulphate, chondroitin-6-sulphate, hyaluronic acid, hyaluronan, keratan sulphate and pentosan polysulphate and oligosaccharides derived from any of the above.

7. The device according to claim 1 , wherein the bioactive factor is bound to the anionic material either directly, indirectly, or indirectly via a linker moiety.

8. The device according to claim 7 , wherein the linker moiety is selected from the group comprising fibronectin, insulin-growth factor binding protein, vitronectin and laminin and peptide derivatives thereof.

9. The device according claim 1 , wherein the chemokine is selected from the group consisting of CXCL12, SDF1β, CCL2 (MCP-1), CCL21, CXCL1, and CXCL8 (IL8), and optionally wherein the agent that inhibits enzymes associated with the breakdown or catabolism of extracellular matrix is selected from the group consisting of tissue inhibitor of metalloproteinase-3, osteoprotegerin, Wnt proteins such as Wnt 3a, DNA complexes, DNA plasmid/viral complexes, complexes of RNA, microRNA and derivatives or biologically active fragments thereof.

10. The device according to claim 1 , wherein the stem cell homing or migratory factor is CXCL12.

11. The device according to claim 1 , wherein the plurality of bioactive factors are sequestered at levels in the nanogram/picomole range.

12. The device according to claim 1 , further including a surface modification to include a bioactive agent that enhances osteogenic function-or a treatment which promotes deposition of hydroxyapatite particles to create an osseous region on the device.

13. The device according to claim 1 , further which is an osteochondral device purposed to aid implant fixation for the regeneration of articular cartilage and underlying subchondral bone which may be fabricated of different biomaterials composing the chondral and osseous regions.

14. A method of making the device of claim 13 , comprising electrospinning a chondral scaffold onto an osseous scaffold or by physically attaching a chondral portion to an osseous region.

15. A method of constructing the acellular biomimetic medical device of claim 1 , comprising:
(i) providing a scaffold core;
(ii) coating a surface of the scaffold core or impregnating the surface of the scaffold core with a first layer comprising a cationic agent;
(iii) covering the first layer of with a second layer comprising an anionic oligosaccharide or polysulphated moiety; and
(iv) attaching a mixture of a plurality of bioactive factors non-covalently either directly to said second layer or indirectly via a linker moiety to said second layer, wherein the plurality of bioactive factors comprises:
a) an agent that can stimulate stem cell differentiation and/or promote appropriate extracellular matrix formation for the tissue to be regenerated selected from the transforming growth factor β group; and
b) a stem cell homing or migratory factor which is a chemokine; and optionally
c) an agent that inhibits enzymes associated with the breakdown or catabolism of extracellular matrix.

16. The method according to claim 15 , wherein the scaffold comprises a non-woven porous material.

17. The method according to claim 15 , wherein the surface of the scaffold core is coated or covered with the first layer comprising the cationic agent by plasma polymerisation.

18. A method of promoting mesenchymal stem cell differentiation into an appropriate cell type for tissue regeneration and/or promoting appropriate extracellular matrix formation and/or inhibiting enzymes associated with the breakdown or catabolism of extracellular matrix or the cartilage matrix and/or encouraging stem cell homing into a tissue defect to promote tissue regeneration and/or treating or promoting healing of an injured joint surface, or an early osteoarthritic lesion, and promoting healing of bone, meniscal cartilage, tendon and/or ligament injuries in a subject in need thereof, the method comprising implanting the device according to claim 1 into an area of a joint or other area of the subject.

19. The method according to claim 18 , wherein the joint is a synovial joint.

20. The method according to claim 16 , wherein the material is electrospun poly-L-lactic acid or polyglycolic acid-poly-L-lactic acid co-polymers or polycaprolactone polymers.

21. The device according to claim 1 , wherein the agent that can stimulate stem cell differentiation and/or promote appropriate extracellular matrix formation for the tissue to be regenerated is TGFβ3.

Assignees

• Univ Sheffield

Inventors

• Crawford-Corrie Aileen
• Buttle David John
• Haycock John William

Classifications

• A61L2300/608

  having two or more layers · CPC title

• A61L27/18

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds · CPC title

• A61L27/56

  Porous materials, {e.g. foams or sponges} · CPC title

• A61L2300/414

  Growth factors · CPC title

• A61L27/34

  Macromolecular materials · CPC title