Compositions and methods for improving mechanical properties of a tissue or for regenerating an injured or diseased tissue
The present invention relates to enhancing mechanical properties of tissue such as collagenous or collagen-containing or elastin-containing tissue (e.g., tendons, ligaments, and cartilage) and treating related musculoskeletal and non-musculoskeletal conditions or injuries.
1. A pharmaceutical composition comprising
(i) lysyl oxidase (LOX) or LOX like (LOXL) protein (LOX/LOXL) enhancer selected from the group consisting of a LOX polypeptide, a LOXL protein, a pre-proLOX polypeptide, a proLOX polypeptide, a nucleic acid encoding one or more of the polypeptides, an engineered cell expressing or having said nucleic acid, and a viral particle having the nucleic acid,
(ii) an agent selected from the group consisting of BMP-1, Fibronectin, Tolloid, Vitamin B6, Ascorbic acid, and Procollagen c proteinase, and
(iii) a pharmaceutically acceptable carrier or excipient.
2. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated in an ointment, a salve, a gel, a cream, a scaffold, or a microparticle.
3. A kit comprising
a LOX/LOXL enhancer selected from the group consisting of a LOX polypeptide, a LOXL protein, a pre-proLOX polypeptide, a proLOX polypeptide, a nucleic acid encoding one or more of the polypeptides, an engineered cell expressing or having said nucleic acid, and a viral particle having the nucleic acid,
an agent selected from the group consisting of BMP-1, Fibronectin, Tolloid, Vitamin B6, Ascorbic acid, and Procollagen c proteinase, and
a packaging material.
4. A method for (i) improving a mechanical property of a tissue or a component thereof in a subject or (ii) regenerating an injured or diseased tissue or developing embryonic/fetal tissue or a component thereof in a subject or (iii) enhancing mechanical properties of a healthy tissue in a subject, comprising (a) applying a mechanical stimulation to the tissue or cells therein and (b) administering to the subject the pharmaceutical composition of claim 1 .
5. The method of claim 4 , wherein said mechanical stimulation comprises one or more of a dynamic stimulation, a cyclic stimulation, a static stimulation, a deformation, a tensile stimulation, a compressive stimulation, a torsion stimulation, a shear stimulation, substrate stiffness, a mechanical loading, a static loading, a dynamic loading, a cyclic loading, a compression, shear, torsion, and deformation.
6. The method of claim 4 , wherein the tissue is a natural tissue, an engineered tissue, an embryonic tissue, a postnatal tissue, a tissue in vitro, or a tissue in vivo.
7. The method of claim 6 , wherein the tissue is a collagenous or collagen-containing tissue.
8. The method of claim 4 , wherein the mechanical property is selected from the group consisting of elastic modulus, tensile strength, torsional strength, elongation to break, hardness, compressive strength, burst strength, toughness, impact strength, torsion, failure load, and stiffness.
9. The method of claim 4 , further comprising administering a population of cells to the tissue.
10. The method of claim 9 , wherein the cells are (i) collagen-producing or elastin-producing cells or progenitor cells thereof or (ii) engineered to release a specific factor that directly or indirectly promotes LOX/LOXL or pro-LOX/pro-LOXL gene expression, LOX/LOXL or pro-LOX/pro-LOXL protein expression, or LOX/LOXL enzyme activity.
11. A method for (i) improving a mechanical property of a tissue or a component thereof in a subject or (ii) regenerating an injured tissue, a diseased or developing embryonic/fetal tissue, or a component thereof in a subject, comprising administering to the subject the pharmaceutical composition of claim 1 .
12. The method of claim 11 , wherein the tissue is a natural tissue, an engineered tissue, a tissue in vitro, or a tissue in vivo.
13. The method of claim 12 , wherein the tissue is a collagenous or collagen-containing tissue or an elastin-containing tissue.
14. The method of claim 11 , wherein the mechanical property is selected from the group consisting of elastic modulus, tensile strength, torsional strength, elongation to break, hardness, compressive strength, burst strength, toughness, impact strength, torsion, failure load, and stiffness.
15. The method of claim 11 , further comprising administering a population of cells to the tissue.
16. The method of claim 15 , wherein the cells are (i) collagen-producing cells, elastin-producing cells or progenitor cells thereof or (ii) engineered to release a specific factor that directly or indirectly promotes LOX/LOXL gene expression, LOX/LOXL protein expression, or LOX/LOXL enzyme activity.
17. The method of claim 4 , wherein this tissue is a tendon tissue or a ligament tissue.
18. The method of claim 11 , wherein this tissue is a tendon tissue or a ligament tissue.