Mechanical and biochemical activation and control of skeletal stem cells for cartilage regeneration
Methods and compositions are provided for the regeneration of articular cartilage by activating skeletal stem cells with a combination of (i) mechanical and (ii) biochemical stimulus. The mechanical stimulus can be an acute local injury. The biochemical stimulus can be a combination of an effective dose of a BMP2 activating agent and a VEGF inhibitor.
1 . A method for regenerating human articular cartilage in a subject with diminished chondrogenesis, the method comprising:
activating human skeletal stem cells with a combination of (i) a mechanical stimulus, and (ii) a biochemical stimulus,
wherein the mechanical stimulus is a surgically performed microfracture procedure to bone tissue at a desired site for articular cartilage regeneration; and
wherein the biochemical stimulus is a combination of an effective dose of human BMP2 protein and a VEGF inhibitor.
2 . The method of claim 1 , wherein the biochemical stimulus is provided within 3 days of the mechanical stimulus.
3 . The method of claim 1 , wherein the VEGF inhibitor is cabozantinib.
4 . The method of claim 1 , wherein the human BMP2 protein and the VEGF inhibitor are provided in a drug delivery device.
5 . The method of claim 4 , wherein the drug delivery device comprises the human BMP2 protein and the VEGF inhibitor as the sole active agents.
6 . The method of claim 4 , wherein the drug delivery device is a biodegradable implant.
7 . The method of claim 6 , wherein the biodegradable implant is a block polymer implant.
8 . The method of claim 6 , wherein the biodegradable implant comprises poly(caprolactone) (PCL), poly(lactic acid) (PLA) or poly(lactic-co-glycolic acid) (PLGA).
9 . The method of claim 6 , wherein the biodegradable implant comprises one or more of polyethylene glycol, alginate, collagen, hyaluronic acid, cellulose, chitosan, silk, gelatin, albumin, or elastin.
10 . The method of claim 6 , wherein the biodegradable implant is a hydrogel.
11 . The method of claim 4 , wherein the drug delivery device is implanted at the site undergoing the surgically performed microfracture procedure in the absence of exogenous cells.
12 . A method for regenerating human articular cartilage in an aged human, the method comprising:
activating human skeletal stem cells with a combination of (i) a mechanical stimulus, and (ii) a biochemical stimulus,
wherein the mechanical stimulus is a surgically performed microfracture procedure to bone tissue at a desired site for articular cartilage regeneration;
wherein the biochemical stimulus is a combination of an effective dose of human BMP2 protein and a VEGF inhibitor, wherein human BMP2 protein is provided at a dose of from about 10 μg to 10 mg, and the VEGF inhibitor is provided at a dose of from about 0.1 μg to 50 mg; and
wherein the biochemical stimulus is provided within 3 days of the mechanical stimulus.
13 . The method of claim 12 , wherein the VEGF inhibitor is cabozantinib.
14 . A method for regenerating human articular cartilage in an individual with osteoarthritis, the method comprising:
activating human skeletal stem cells with a combination of (i) a mechanical stimulus, and (ii) a biochemical stimulus,
wherein the mechanical stimulus is a surgically performed microfracture procedure to bone tissue at a desired site for articular cartilage regeneration;
wherein the biochemical stimulus is a combination of an effective dose of human BMP2 protein and a VEGF inhibitor, wherein the human BMP2 protein is provided at a dose of from about 10 μg to 10 mg, and the VEGF inhibitor is provided at a dose of from about 0.1 μg to 50 mg; and
wherein the biochemical stimulus is provided within 3 days of the mechanical stimulus.
15 . The method of claim 14 , wherein the VEGF inhibitor is cabozantinib.