Micro- and nano-device for cartilage injury detection and treatment
The present invention provides targeting probe, imaging probes, and probes for use as a medicament to treat damaged cartilage, where the probe targets injured tissue and can then be imaged and/or release agents to trigger the migration of surrounding chondrocytes from healthy tissue to injured tissue and/or recruit synovial stem cells.
1. An arthritic cartilage targeting probe comprising:
a biocompatible hyaluronic acid polymer crosslinked by a vinyl sulfone to form a crosslinked biopolymer, wherein the biocompatible hyaluronic acid polymer has a molecular weight of 10K to 1.5M and the crosslinking ratio of the biocompatible HA polymer:vinyl sulfone is between 4:1 and 1:4 and the crosslinked biopolymer has a diameter of about 200 to 500 nm to modulate internalization;
a ligand in contact with the crosslinked biopolymer, wherein the ligand is hyaluronic acid that interacts with a CD44 receptor, folic acid that interacts with a folate receptor or both; and
a detectable tag in contact with the crosslinking agent, first biocompatible polymer, the ligand or a combination thereof, wherein the probe triggers stem cell recruitment, differentiation, and cartilage regeneration.
2. A damaged cartilage targeting probe comprising:
a biocompatible hyaluronic acid polymer crosslinked by a vinyl sulfone to form a crosslinked biopolymer, wherein the biocompatible hyaluronic acid polymer has a molecular weight of 10K to 1.5M and the crosslinking ratio of the biocompatible HA polymer:vinyl sulfone is between 4:1 and 1:4 and the crosslinked biopolymer has a diameter of about 200 to 500 nm to modulate internalization;
a ligand in contact with the crosslinked biopolymer, wherein the ligand interacts with one or more cell surface targets; and
a detectable tag in contact with the crosslinking agent, first biocompatible polymer, the ligand or a combination thereof, wherein the probe triggers stem cell recruitment, differentiation, and cartilage regeneration.
3. A method for identifying damaged cartilage comprising:
providing a damaged cartilage targeting probe that comprises a biocompatible hyaluronic acid polymer crosslinked by a vinyl sulfone crosslinking agent to form a crosslinked biopolymer, wherein the biocompatible hyaluronic acid polymer has a molecular weight of 10K to 1.5M and the crosslinking ratio of the biocompatible polymer:crosslinking agent is between 4:1 and 1:4; wherein the crosslinked biopolymer has a diameter of about 200 to 500 nm to modulate internalization; a ligand in contact with the crosslinked biopolymer, wherein the ligand interacts with one or more cell surface targets; and a detectable tag in contact with the crosslinking agent, first biocompatible polymer, the ligand or a combination thereof;
contacting a cartilage suspected of being damaged with the damaged cartilage targeting probe; and
detecting the damaged cartilage targeting probe.
4. A cartilage targeting probe to treat damaged cartilage by recruiting stem cells, chondrocytes or both to the damaged cartilage, wherein the cartilage targeting probe comprises:
a biocompatible hyaluronic acid polymer crosslinked by a vinyl sulfone crosslinking agent to form a crosslinked biopolymer, wherein the biocompatible hyaluronic acid polymer has a molecular weight of 10K to 1.5M and the crosslinking ratio of the biocompatible polymer:crosslinking agent is between 4:1 and 1:4 and the crosslinked biopolymer has a diameter of about 200 to 500 nm to modulate internalization;
a ligand in contact with the crosslinked biopolymer, wherein the ligand interacts with one or more cell surface targets;
one or more chemokines selected from SDF 1, SDF 1β, Epo, CCL2, CCL16, VEGF, TGF-β1 and TGF-β3, associated with the polymer targeting probe, wherein the one or more chemokines are released to recruit stem cells, chondrocytes or both; and
a detectable tag in contact with the crosslinking agent, first biocompatible polymer, the ligand or a combination thereof.
5. A cartilage targeting probe to treat damaged cartilage by increasing chondrogenic differentiation, wherein the cartilage targeting probe comprises:
a biocompatible hyaluronic acid polymer crosslinked by a vinyl sulfone crosslinking agent to form a crosslinked biopolymer, wherein the biocompatible hyaluronic acid polymer has a molecular weight of 10K to 1.5M and the crosslinking ratio of the biocompatible polymer:crosslinking agent is between 4:1 and 1:4 and the crosslinked biopolymer has a diameter of about 200 to 500 nm to modulate internalization;
a ligand in contact with the crosslinked biopolymer, wherein the ligand interacts with one or more cell surface targets;
one or more TGF active agents selected from TGF-β1 and TGF-β3 associated with the polymer targeting probe, wherein the one or more TGF active agents are released to trigger higher chondrogenic differentiation; and
a detectable tag in contact with the crosslinking agent, first biocompatible polymer, the ligand or a combination thereof, wherein the probe triggers stem cell recruitment, differentiation, and cartilage regeneration.
6. The arthritic cartilage targeting probe of claim 1 , wherein the ligand is hyaluronic acid and the one or more cell surface targets is a CD44 receptor.
7. The arthritic cartilage targeting probe of claim 1 , wherein the ligand is a folic acid and the one or more cell surface targets is a folate receptor.
8. The arthritic cartilage targeting probe of claim 1 , wherein the damaged cartilage is from mechanical trauma, physical trauma compression trauma, arthritic damage, inflammatory damage or a combination thereof.
9. The arthritic cartilage targeting probe of claim 1 wherein the molecular weight is about 10K, 60K, 700k, 1.5M or incremental variations thereof.
10. The arthritic cartilage targeting probe of claim 1 , wherein the crosslinking ratio is 1:4, 1:3, 1:2, 1:1, 1:3.9, 1:3.5, 1:2.3, 4:1, 3:1, 2:1 and incremental variations thereof.
11. The arthritic cartilage targeting probe of claim 1 , wherein the detectable tag is a fluorescent dye, a radioactive tag, a metal, a nanoparticle or a combination thereof.
12. The arthritic cartilage targeting probe of claim 1 , wherein the polymer targeting probe is biodegradable.
13. The arthritic cartilage targeting probe of claim 4 , wherein the one or more chemokines or one or more TGF active agents are bound to the crosslinked biopolymer, releasably associated, disposed in the crosslinked biopolymer, spray coated on the crosslinked biopolymer or a combination thereof.
14. The arthritic cartilage targeting probe of claim 4 wherein the crosslinked biopolymer comprises one or more pores and the one or more chemokines or one or more TGF active agents are disposed in the one or more pores for extended release over time.
15. The arthritic cartilage targeting probe of claim 14 , wherein the one or more pores have a diameter of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 nm or less than 1 nm or greater than 29 nm.
16. The arthritic cartilage targeting probe of claim 1 , wherein the polymer targeting probe contacts the one or more targets in less than 15 minutes to allow the quick detection within 15 minutes.
17. The arthritic cartilage targeting probe of claim 1 , the polymer targeting probe is intra-articular injected.
18. The arthritic cartilage targeting probe of claim 1 , wherein the targeting probe is used to image the damaged/injured cartilage and deliver one or more active agents to the damaged/injured cartilage.
19. A damaged/injured cartilage imaging probe for use as a medicament to target and/or treat damaged cartilage, wherein the damaged cartilage imaging probe comprises
a biocompatible hyaluronic acid polymer crosslinked by a vinyl sulfone to form a crosslinked biopolymer, wherein the biocompatible hyaluronic acid polymer has a molecular weight of 10K to 1.5M and the crosslinking ratio of the biocompatible HA polymer:vinyl sulfone is between 4:1 and 1:4 and the crosslinked biopolymer has a diameter of about 200 to 500 nm to modulate internalization;
a ligand in contact with the crosslinked biopolymer, wherein the ligand is hyaluronic acid that interacts with a CD44 receptor, folic acid that interacts with a folate receptor or both; and
a detectable tag in contact with the crosslinking agent, first biocompatible polymer, the ligand or a combination thereof, wherein the detectable tag can be detected at the damaged cartilage and used to generate an image of the damaged cartilage, wherein the probe triggers stem cell recruitment, differentiation, and cartilage regeneration.
20. A damaged cartilage probe for use as a medicament for targeted treatment of damaged cartilage, wherein the damaged cartilage probe comprises:
a cartilage damaged imaging probe for identifying damaged cartilage, wherein the cartilage damaged imaging probe comprises a biocompatible hyaluronic acid polymer crosslinked by a vinyl sulfone to form a crosslinked biopolymer, wherein the biocompatible hyaluronic acid polymer has a molecular weight of 10K to 1.5M and the crosslinking ratio of the biocompatible HA polymer:vinyl sulfone is between 4:1 and 1:4 and the crosslinked biopolymer has a diameter of about 200 to 500 nm to modulate internalization; a ligand in contact with the crosslinked biopolymer, wherein the ligand is hyaluronic acid that interacts with a CD44 receptor, folic acid that interacts with a folate receptor or both; and a detectable tag in contact with the crosslinking agent, first biocompatible polymer, the ligand or a combination thereof, wherein the detectable tag can be detected at the damaged cartilage and used to generate an image of the damaged cartilage; and
a cartilage targeting probe for use as a medicament to treat damaged cartilage by recruiting stem cells, chondrocytes or both to the damaged cartilage, wherein the cartilage targeting probe comprises: a biocompatible hyaluronic acid polymer crosslinked by a vinyl sulfone crosslinking agent to form a crosslinked biopolymer, wherein the biocompatible hyaluronic acid polymer has a molecular weight of 10K to 1.5M and the crosslinking ratio of the biocompatible polymer:crosslinking agent is between 4:1 and 1:4 and the crosslinked biopolymer has the diameter of about 200 to 500 nm to modulate internalization; a ligand in contact with the crosslinked biopolymer, wherein the ligand interacts with one or more cell surface targets; one or more chemokines selected from SDF 1, SDF 1β, Epo, CCL2, CCL16, VEGF, TGF-β1 and TGF-β3, associated with the polymer targeting probe, wherein the one or more chemokines are released to recruit stem cells, chondrocytes or both; and optionally a second detectable tag in contact with the crosslinking agent, first biocompatible polymer, the ligand or a combination thereof; and optionally a chondrogenic differentiation probe for use as a medicament to treat damaged cartilage by increasing chondrogenic differentiation, wherein the chondrogenic differentiation probe comprises: a biocompatible hyaluronic acid polymer crosslinked by a vinyl sulfone crosslinking agent to form a crosslinked biopolymer, wherein the biocompatible hyaluronic acid polymer has a molecular weight of 10K to 1.5M and the crosslinking ratio of the biocompatible polymer:crosslinking agent is between 4:1 and 1:4 and the crosslinked biopolymer has a diameter of greater than about 200 nm to modulate internalization; a ligand in contact with the crosslinked biopolymer, wherein the ligand interacts with one or more cell surface targets; one or more TGF active agents selected from TGF-β1 and TGF-β3 associated with the polymer targeting probe, wherein the one or more TGF active agents are released to trigger higher chondrogenic differentiation; and a third detectable tag in contact with the crosslinking agent, first biocompatible polymer, the ligand or a combination thereof, wherein the probe triggers stem cell recruitment, differentiation, and cartilage regeneration.