Micro- and nano-device for cartilage injury detection and treatment

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.

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.

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.

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.

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.

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.