WO2011154882A1 - Induction of bone formation - Google Patents

Induction of bone formation Download PDF

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Publication number
WO2011154882A1
WO2011154882A1 PCT/IB2011/052436 IB2011052436W WO2011154882A1 WO 2011154882 A1 WO2011154882 A1 WO 2011154882A1 IB 2011052436 W IB2011052436 W IB 2011052436W WO 2011154882 A1 WO2011154882 A1 WO 2011154882A1
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bone formation
mammal
inducing
epidural
bone
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PCT/IB2011/052436
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French (fr)
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Ugo Ripamonti
Carlo Ferretti
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University Of The Witwatersrand, Johannesburg
Medical Research Council Of South Africa
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Publication of WO2011154882A1 publication Critical patent/WO2011154882A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1841—Transforming growth factor [TGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders

Definitions

  • the invention relates to the role tissue segregation in restoring the induction of bone formation by the mammalian transforming growth factor- ⁇ isoforms in primates.
  • TGF- ⁇ transforming growth factor- ⁇
  • TGF- ⁇ transforming growth factor- ⁇
  • selected proteins of the TGF- ⁇ supergene family induce/control the induction of bone formation.
  • the bone morphogenetic/osteogenic proteins (BMPs/OPs), remarkably, induce de novo bone formation in heterotopic extra-skeletal sites of a variety of animal models including non-human and human primates (Reddi 2000; Ripamonti 2006; Ripamonti et al. 2000; Ripamonti et al. 2006).
  • Systematic studies in the non-human primate Papio ursinus have however shown that the three mammalian TGF- ⁇ proteins are endowed with the striking prerogative of inducing endochondral bone differentiation when implanted heterotopically in extraskeletal sites of the rectus abdominis muscles of adult non-human primates Papio ursinus (Ripamonti et al 1997; Ripamonti et al 2000; Ripamonti et al 2008; Ripamonti and Roden 2010).
  • a method of inducing bone formation in an epidural location of a mammal comprising positioning, over the dural area of a mammalian body where bone induction is desired, a substantially fluid impermeable physical barrier and introducing, into the area between the dura and existing bony tissue where bone formation is desired, a transforming growth factor- ⁇ isoform.
  • the bony tissue is calvarial bone.
  • the barrier is implanted, preferably surgically, into the area of the mammalian body where bone induction is desired.
  • the barrier is also provided for the barrier to be a substantially fluid impermeable membrane and for the membrane to be formed from a synthetic plastics material, preferably Supramid.
  • the transforming growth factor- ⁇ isoform to be TGF-3 3
  • a suitable substrate either by incorporating it into or applying it to the surface of the substrate which may be a macroporous calcium carbonate, alternatively hydroxyapatite, construct, further alternatively a gel, preferably Matrigel.
  • the invention extends to a substantially fluid impermeable physical barrier for use in a method of inducing epidural bone formation in a mammal said method comprising positioning the barrier over the dura in an area of a mammalian body where bone induction is desired and introducing, into the area where bone induction is desired, a transforming growth factor- ⁇ isoform.
  • the barrier is also provided for the barrier to be a substantially fluid impermeable membrane and for the membrane to be formed from a synthetic plastics material, preferably Supramid.
  • the barrier is further provided for the barrier to be implanted, preferably surgically, over the area of the mammalian body where bone induction is desired.
  • the transforming growth factor- ⁇ isoform to be TGF-3 3
  • a suitable substrate either by incorporating it into or applying it to the surface of the substrate which may be a macroporous calcium bicarbonate, alternatively hydroxyapatite, construct, further alternatively a gel, preferably Matrigel.
  • the invention also extends to a kit for use in inducing epidural bone formation at a desired location in a mammalian body said kit comprising a substantially fluid - .it - impermeable physical barrier which is positionable over an area of a mammalian body where bone Induction Is desired and a transforming growth fador- ⁇ isoform which is introducible into the area where bone Induction Is desired after the barrier has been positioned.
  • the barrier is also provided for the barrier to be a substantially fluid impermeable membrane and for the membrane to be formed from a synthetic plastics material, preferably Supramid and for the barrier to be positioned by implantation, preferably surgically, over the area of the mammalian body where bone induction is desired.
  • the transforming growth factor- ⁇ isoform to be TGF-(3 3l and for the tranafbrming growth factor- ⁇ Isoform to be used In conjunction with a suitable substrate, either by incorporating it into or applying it to the surface of the substrate which may be a macroporous calcium bicarbonate, alternatively hydroxyapatite, construct, further alternatively a gel, preferably Matrigel.
  • a suitable substrate either by incorporating it into or applying it to the surface of the substrate which may be a macroporous calcium bicarbonate, alternatively hydroxyapatite, construct, further alternatively a gel, preferably Matrigel.
  • Figure 1 is a light micrograph of limited calvarial bone induction in a non-human primate, Papfo ursinus when a substantially fluid impermeable physical barrier according to the Invention Is not used;
  • Figure 2 ie a light micrograph of calvarial bone induction in Papfo ursinus when a substantially fluid impermeable physical barrier according to the invention is used, here the membrane has been inserted just above the dura mater covering the brain.
  • tissue segregation of the calvarial defect restores the biological activity of a mammalian transforming growth factor- ⁇ ; the inventive steps further indicate that the dura mater and/or leptomeninges secrete gene products that set into motion the expression of the Inhibitory Smad proteins Smad-6 and -7 that inhibit the induction of bone formation by the mammalian TGF- ⁇ proteins. It is further envisaged that this will have important implications for the use of the hTGF-3 3 isoform in craniofacial reconstruction in human patients.
  • the abovedescribed invention can be used to induce bone formation in any location of the mammalian body in which the dura separates the bony tissue from underlying soft tissue such as the vertebrae and sinuses.
  • the method of use of the invention will, it is envisaged, be substantially the same as described above.
  • Ripamonti U Ferretti C, Heliotis M. Soluble and insoluble signals and the induction of bone formation: molecular therapeutics recapitulating development. J Anat 2006;209:447-68. Ripamonti U, van den Heever B, Crooks J, Rueger DC, Reddi AH. Long-term evaluation of bone formation by osteogenic protein 1 in the baboon and relative efficacy of bone-derived bone morphogenetic proteins delivered by irradiated xenogeneic collagenous matrices. J Bone Miner Res. 2000; 15: 1798-809. Ripamonti U. Soluble osteogenic molecular signals and the induction of bone formation.

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Abstract

This invention relates to a method of inducing epidural bone formation in a mammal, to a substantially fluid impermeable physical barrier for use said method of inducing epidural bone formation in a mammal and a kit for use in inducing epidural bone formation at a desired location in a mammalian body. The method involves positioning, over the dural area of a mammalian body where bone induction is desired, a substantially fluid impermeable physical barrier and introducing, into the area between the dura and existing bony tissue where bone formation is desired, a transforming growth factor-β isoform. The barrier is, preferably, a synthetic plastics material membrane and the transforming growth factor-β isoform is TGF-β3 which is used in conjunction with a suitable substrate.

Description

INDUCTION OF BONE FORMATION
FIELD OF THE INVENTION
The invention relates to the role tissue segregation in restoring the induction of bone formation by the mammalian transforming growth factor-β isoforms in primates.
BACKGROUND TO THE INVENTION
Secreted gene products/proteins of the transforming growth factor-β (TGF-β) supergene family induce a vast and pleiotropic range of biological activities, which include cell proliferation, differentiation, extracellular matrix formation and remodelling and more broadly pattern formation, tissue induction, morphogenesis and organogenesis (Reddi 2000; Ripamonti 2006). In addition to the above, selected proteins of the TGF-β supergene family induce/control the induction of bone formation. Amongst the secreted proteins of the TGF-β supergene family, the bone morphogenetic/osteogenic proteins (BMPs/OPs), remarkably, induce de novo bone formation in heterotopic extra-skeletal sites of a variety of animal models including non-human and human primates (Reddi 2000; Ripamonti 2006; Ripamonti et al. 2000; Ripamonti et al. 2006).
The three mammalian TGF-β isoforms, members of the TGF-β superfamily, do not initiate the induction of bone formation when implanted in heterotopic extraskeletal sites of a variety of animal models (Ripamonti 2006). Systematic studies in the non-human primate Papio ursinus have however shown that the three mammalian TGF-β proteins are endowed with the striking prerogative of inducing endochondral bone differentiation when implanted heterotopically in extraskeletal sites of the rectus abdominis muscles of adult non-human primates Papio ursinus (Ripamonti et al 1997; Ripamonti et al 2000; Ripamonti et al 2008; Ripamonti and Roden 2010).
On the other hand, it has also been found that orthotopic calvarial implantation of the three mammalian TGF-β isoforms in the same animals with identical and/or higher doses of the recombinant proteins does not induce bone formation on day 30 (Ripamonti et al 1996; Ripamonti et al 2000; Ripamonti et al 2008; Ripamonti and Roden 2010). On day 90 after implantation and in some specimens only, there is limited pericranial bone formation across the defects implanted with the mammalian TGF-β proteins (Ripamonti et al 2000; Ripamonti et al 2008; Ripamonti and Roden 2010).
OBJECT OF THE INVENTION
It is an object of this invention to provide a method of inducing bone formation using a TGF-β isoform in a mammal, a substantially fluid impermeable physical barrier for use in a method of inducing bone formation in a mammal and a kit for use in inducing bone formation at a desired location in a mammalian body.
SUMMARY OF THE INVENTION
In accordance with this invention there is provided a method of inducing bone formation in an epidural location of a mammal comprising positioning, over the dural area of a mammalian body where bone induction is desired, a substantially fluid impermeable physical barrier and introducing, into the area between the dura and existing bony tissue where bone formation is desired, a transforming growth factor-β isoform.
There is further provided for the bony tissue to be calvarial bone. There is further provided for the barrier to be implanted, preferably surgically, into the area of the mammalian body where bone induction is desired.
There is also provided for the barrier to be a substantially fluid impermeable membrane and for the membrane to be formed from a synthetic plastics material, preferably Supramid.
There is further provided for the transforming growth factor-β isoform to be TGF-33, and for the transforming growth factor-β isoform to be used in conjunction with a suitable substrate, either by incorporating it into or applying it to the surface of the substrate which may be a macroporous calcium carbonate, alternatively hydroxyapatite, construct, further alternatively a gel, preferably Matrigel.
The invention extends to a substantially fluid impermeable physical barrier for use in a method of inducing epidural bone formation in a mammal said method comprising positioning the barrier over the dura in an area of a mammalian body where bone induction is desired and introducing, into the area where bone induction is desired, a transforming growth factor-β isoform. There is also provided for the barrier to be a substantially fluid impermeable membrane and for the membrane to be formed from a synthetic plastics material, preferably Supramid.
There is further provided for the barrier to be implanted, preferably surgically, over the area of the mammalian body where bone induction is desired.
There is further provided for the transforming growth factor-β isoform to be TGF-33, and for the transforming growth factor-β isoform to be used in conjunction with a suitable substrate, either by incorporating it into or applying it to the surface of the substrate which may be a macroporous calcium bicarbonate, alternatively hydroxyapatite, construct, further alternatively a gel, preferably Matrigel.
The invention also extends to a kit for use in inducing epidural bone formation at a desired location in a mammalian body said kit comprising a substantially fluid - .it - impermeable physical barrier which is positionable over an area of a mammalian body where bone Induction Is desired and a transforming growth fador-β isoform which is introducible into the area where bone Induction Is desired after the barrier has been positioned.
There is also provided for the barrier to be a substantially fluid impermeable membrane and for the membrane to be formed from a synthetic plastics material, preferably Supramid and for the barrier to be positioned by implantation, preferably surgically, over the area of the mammalian body where bone induction is desired.
There is further provided for the transforming growth factor-β isoform to be TGF-(33l and for the tranafbrming growth factor-β Isoform to be used In conjunction with a suitable substrate, either by incorporating it into or applying it to the surface of the substrate which may be a macroporous calcium bicarbonate, alternatively hydroxyapatite, construct, further alternatively a gel, preferably Matrigel.
BRIEF DESCRIPTION OF THE DRAWINGS The above and additional features of the invention will become apparent from the accompanying description and light micrographs in which;
Figure 1 is a light micrograph of limited calvarial bone induction in a non-human primate, Papfo ursinus when a substantially fluid impermeable physical barrier according to the Invention Is not used; and
Figure 2 ie a light micrograph of calvarial bone induction in Papfo ursinus when a substantially fluid impermeable physical barrier according to the invention is used, here the membrane has been inserted just above the dura mater covering the brain.
DESCRIPTION OF PREFERRED EMBODIMENTS
In response to the observation that, despite the three mammalian TGF-B proteins or isoforms being endowed with the striking prerogative of inducing endochondral bone differentiation when implanted heterotopically in extraskeletal sites of the rectus abdominis muscles of adult non-human primates Pepio ursinus, there was only limited pericranial bone formation across the defects implanted with the identical and/or higher doses of the mammalian TGF-β proteins in the same animals, the applicants hypothesized that the inhibitory Smad-6 and -7 over-expression in TGF-ps treated calvarial defects is due to the vascular endothelial network of the arachnoids expressing eignalling proteins modulating the expression of the inhibitory Smads in pre-osteoblastic and osteoblastic calvarial cell lines ultimately controlling the induction of bone formation in the in the primate calvarium.
This diffusion molecular hypothesis was thus tested by surgically inserting an Impermeable membrane below the endocranium and above the dura and the arachnoids thus segregating the molecular and cellular macro and/or microenvironments of the calvarial defects from the dura and leptomeninges below. The applicants show that segregation restores the previously unreported and novel induction of bone formation endocranially by a mammalian TGF-β isofprm just above the implanted polyamide membranes and the segregated meninges.
The result of this test is clearly seen in the accompanying light micrographs (Figure 1) and (Figure 2). In these micrographs (Figure 1) shows that implantation of doses of hTGF-p, (human transformation growth factor-pj) in calvarial defects does not result In the induction of bone formation across the macroporoue spaces and that bone induction is predominantly confined to the pericranial regions of the specimens only. In contrast, light micrograph (Figure 2) the insertion or implantation of a substantially fluid impermeable Supramid membrane above the meninges thus isolating the dura matter and the arachnoids below restores the biological activity of the hTGF-βι isoform with bone induction across the macroporoue spaces.
It is hypothesised that the above use of the calvarial defect model of the non-human primate Papio ursinus has shown that tissue segregation of the calvarial defect restores the biological activity of a mammalian transforming growth factor-β; the inventive steps further indicate that the dura mater and/or leptomeninges secrete gene products that set into motion the expression of the Inhibitory Smad proteins Smad-6 and -7 that inhibit the induction of bone formation by the mammalian TGF-β proteins. It is further envisaged that this will have important implications for the use of the hTGF-33 isoform in craniofacial reconstruction in human patients.
It is also envisaged that the abovedescribed invention can be used to induce bone formation in any location of the mammalian body in which the dura separates the bony tissue from underlying soft tissue such as the vertebrae and sinuses. In such instances the method of use of the invention will, it is envisaged, be substantially the same as described above.
REFERENCES
Reddi AH. Morphogenesis and tissue engineering of bone and cartilage: Inductive signals, stem cells, and biomimetic biomaterials. Tissue Eng. 2000; 6: 351 -9.
Ripamonti U, Ferretti C, Heliotis M. Soluble and insoluble signals and the induction of bone formation: molecular therapeutics recapitulating development. J Anat 2006;209:447-68. Ripamonti U, van den Heever B, Crooks J, Rueger DC, Reddi AH. Long-term evaluation of bone formation by osteogenic protein 1 in the baboon and relative efficacy of bone-derived bone morphogenetic proteins delivered by irradiated xenogeneic collagenous matrices. J Bone Miner Res. 2000; 15: 1798-809. Ripamonti U. Soluble osteogenic molecular signals and the induction of bone formation.
Biomaterials. 2006; 27: 807-22.
Ripamonti U, Bosch C, van den Heever B, Duneas N, Melsen B, Ebner R. Limited chondro-osteogenesis by recombinant human transforming growth factor^ in calvarial defects of adult baboons (Papio ursinus). J Bone Miner Res.
1996; 1 1 : 938 945.
Ripamonti U, Duneas N, van den Heever B, Bosch C, Crooks J. Recombinant transforming growth factor^ induces endochondral bone in the baboon and synergizes with recombinant osteogenic protein-1 (bone morphogenetic protein-7) to initiate rapid bone formation. J Bone Miner Res. 1997; 2: 1584- 95.
Ripamonti U, Crooks J, Matsaba T, Tasker J. Induction of endochondral bone formation by recombinant human transforming growth factor-32 in the baboon (Papio ursinus). Growth Factors. 2000; 17: 269-85.
Ripamonti U, Ramoshebi LN, Teare J, Renton L, Ferretti C. The induction of endochondral bone formation by transforming growth factor-33: experimental studies in the non-human primate Papio ursinus. J Cell Mol Med. 2008; 12: 1029-48.
Ripamonti U, Roden L. The induction of bone formation by transforming growth
factor-32 in the non-human primate Papio ursinus and its modulation by skeletal muscle responding stem cells. Cell Prolif. 2010; 43: 207-218.

Claims

A method of inducing bone formation in an epidural location of a mammal comprising positioning, over the dural area of a mammalian body where bone induction is desired, a substantially fluid impermeable physical barrier and introducing, into the area between the dura and existing bony tissue where bone formation is desired, a transforming growth factor-β isoform.
A method of inducing bone formation in an epidural location of a mammal as claimed in claim 1 in which the bony tissue is calvarial bone.
A method of inducing bone formation in an epidural location of a mammal as claimed in claim 1 or in claim 2 in which the barrier is implanted into the area of the mammalian body where bone induction is desired.
A method of inducing bone formation in an epidural location of a mammal as claimed in claim 3 in which the barrier is surgically implanted into the area of the mammalian body where bone induction is desired.
A method of inducing bone formation in an epidural location of a mammal as claimed in any one of the preceding claims in which the barrier is a substantially fluid impermeable membrane.
6. A method of inducing bone formation in an epidural location of a mammal as claimed in 5 in which the membrane is formed from a synthetic plastics material.
7. A method of inducing bone formation in an epidural location of a mammal as claimed in claim 6 in which the synthetic plastics material is Supramid.
8. A method of inducing bone formation in an epidural location of a mammal as claimed in any one of the preceding claims in which the transforming growth factor-β isoform is TGF-33.
9. A method of inducing bone formation in an epidural location of a mammal as claimed in any one of the preceding claims in which the transforming growth factor-β isoform is used in conjunction with a suitable substrate.
10. A method of inducing bone formation in an epidural location of a mammal as claimed in claim 9 in which the transforming growth factor-β isoform is incorporated into or applied to the surface of the substrate.
1 1 . A method of inducing bone formation in an epidural location of a mammal as claimed in claim 9 or in claim 10 in which the substrate is a macroporous calcium carbonate construct.
12. A method of inducing bone formation in an epidural location of a mammal as claimed in claim 9 or in claim 10 in which the substrate is a hydroxyapatite, construct.
13. A method of inducing bone formation in an epidural location of a mammal as claimed in claim 9 or in claim 10 in which the substrate is a gel.
14. A method of inducing bone formation in an epidural location of a mammal as claimed in claim 13 in which the gel is Matrigel.
15. A substantially fluid impermeable physical barrier for use in a method of inducing epidural bone formation in a mammal said method comprising positioning the barrier over the dura in an area of a mammalian body where bone induction is desired and introducing, into the area where bone induction is desired, a transforming growth factor-β isoform.
16. A substantially fluid impermeable physical barrier as claimed in claim 15 in which the barrier is a substantially fluid impermeable membrane.
17. A substantially fluid impermeable physical barrier as claimed in claim 16 in which the membrane is formed from a synthetic plastics material.
18. A substantially fluid impermeable physical barrier as claimed in claim 17 in which the membrane is formed from Supramid.
19. A substantially fluid impermeable physical barrier as claimed in any one of claims 15 to 18 in which the barrier is implanted, preferably surgically, over the area of the mammalian body where bone induction is desired.
20. A substantially fluid impermeable physical barrier as claimed in any one of claims 15 to 19 for use in a method of inducing epidural bone formation in a mammal comprising positioning the barrier over the dura in an area of a mammalian body where bone induction is desired and introducing, into the area where bone induction is desired, a transforming growth factor-β isoform which is TGF-33.
21 . A substantially fluid impermeable physical barrier as claimed in claim 20 for use in a method of inducing epidural bone formation in a mammal in which the transforming growth factor-β isoform is used in conjunction with a suitable substrate, either by incorporating it into or applying it to the surface of the substrate.
22. A substantially fluid impermeable physical barrier as claimed in claim 21 for use in a method of inducing epidural bone formation in a mammal in which the substrate is formed from macroporous calcium carbonate.
23. A substantially fluid impermeable physical barrier as claimed in claim 21 for use in a method of inducing epidural bone formation in a mammal in which the substrate is formed from hydroxyapatite.
24. A substantially fluid impermeable physical barrier as claimed in claim 21 for use in a method of inducing epidural bone formation in a mammal in which the substrate is formed from a gel, preferably Matrigel.
25. A kit for use in inducing epidural bone formation at a desired location in a mammalian body said kit comprising a substantially fluid impermeable physical barrier which is positionable over an area of a mammalian body where bone induction is desired and a transforming growth factor-β isoform which is introducible into the area where bone induction is desired after the barrier has been positioned.
26. A kit as claimed in claim 25 in which the barrier is a substantially fluid impermeable membrane.
27. A kit as claimed in claim 26 in which the membrane is formed from a synthetic plastics material, preferably Supramid.
28. A kit as claimed in any one of claims 25 to 27 in which the barrier is positioned by implantation, preferably surgically, over the area of the mammalian body where bone induction is desired.
29. A kit as claimed in any one of claims 25 to 28 in which the transforming growth factor-β isoform is TGF-33.
30. A kit as claimed in any one of claims 25 to 29 in which the transforming growth factor-β isoform is used in conjunction with a suitable substrate, either by incorporating it into or applying it to the surface of the substrate.
31 . A kit as claimed in claim 30 in which the substrate is a macroporous calcium delete carbonate construct.
32. A kit as claimed in claim 30 in which the substrate is hydroxyapatite construct.
33. A kit as claimed in claim 30 in which the substrate is a gel, preferably Matrigel.
PCT/IB2011/052436 2010-06-06 2011-06-03 Induction of bone formation WO2011154882A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003079964A2 (en) * 2002-03-22 2003-10-02 University Of Witwatersrand Composition for stimulating de novo bone induction
WO2007045955A2 (en) * 2005-10-17 2007-04-26 University Of The Witwatersrand, Johannesburg Osteogenic device for inducing bone formation in clinical contexts

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003079964A2 (en) * 2002-03-22 2003-10-02 University Of Witwatersrand Composition for stimulating de novo bone induction
WO2007045955A2 (en) * 2005-10-17 2007-04-26 University Of The Witwatersrand, Johannesburg Osteogenic device for inducing bone formation in clinical contexts

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KAMAKURA S ET AL: "Implantation of octacalcium phosphate combined with transforming growth factor-[beta]1 enhances bone repair as well as resorption of the implant in rat skull defects", JOURNAL OF BIOMEDICAL MATERIALS RESEARCH 2001 JOHN WILEY AND SONS INC. US, vol. 57, no. 2, 2001, pages 175 - 182, XP009153226, DOI: DOI:10.1002/1097-4636(200111)57:2<175::AID-JBM1156>3.0.CO;2-Q *
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RIPAMONTI U ET AL: "LIMITED CHONDRO-OSTEOGENESIS BY RECOMBINANT HUMAN TRANSFORMING GROWTH FACTOR-BETA1 IN CALVARIAL DEFECTS OF ADULT BABOONS (PAPIO URSINUS)", JOURNAL OF BONE AND MINERAL RESEARCH, AMERICAN SOCIETY FOR BONE AND MINERAL RESEARCH, NEW YORK, NY, US, vol. 11, no. 7, 1 January 1996 (1996-01-01), pages 938 - 945, XP009025489, ISSN: 0884-0431 *
RIPAMONTI U ET AL: "Transforming growth factor-[beta] isoforms and the induction of bone formation: Implications for reconstructive craniofacial surgery", JOURNAL OF CRANIOFACIAL SURGERY, BURLINGTON, CA, vol. 20, no. 5, 1 January 2009 (2009-01-01), pages 1544 - 1555, XP009153241, ISSN: 1049-2275 *
RIPAMONTI U, BOSCH C, VAN DEN HEEVER B, DUNEAS N, MELSEN B, EBNER R: "Limited chondro-osteogenesis by recombinant human transforming growth factor-pi in calvarial defects of adult baboons (Papio ursinus", J BONE MINER RES., vol. 11, 1996, pages 938 945
RIPAMONTI U, CROOKS J, MATSABA T, TASKER J.: "Induction of endochondral bone formation by recombinant human transforming growth factor-?2 in the baboon (Papio ursinus", GROWTH FACTORS, vol. 17, 2000, pages 269 - 85, XP009153180
RIPAMONTI U, DUNEAS N, VAN DEN HEEVER B, BOSCH C, CROOKS J: "Recombinant transforming growth factor-pi induces endochondral bone in the baboon and synergizes with recombinant osteogenic protein-1 (bone morphogenetic protein-7) to initiate rapid bone formation", J BONE MINER RES., vol. 2, 1997, pages 1584 - 95, XP008126302, DOI: doi:10.1359/jbmr.1997.12.10.1584
RIPAMONTI U, FERRETTI C, HELIOTIS M: "Soluble and insoluble signals and the induction of bone formation: molecular therapeutics recapitulating development", J ANAT, vol. 209, 2006, pages 447 - 68, XP009153229
RIPAMONTI U, RAMOSHEBI LN, TEARE J, RENTON L, FERRETTI C: "The induction of endochondral bone formation by transforming growth factor-03: experimental studies in the non-human primate Papio ursinus", J CELL MOL MED., vol. 12, 2008, pages 1029 - 48, XP009153183, DOI: doi:10.1111/j.1582-4934.2008.00126.x
RIPAMONTI U, RODEN L: "The induction of bone formation by transforming growth factor-02 in the non-human primate Papio ursinus and its modulation by skeletal muscle responding stem cells", CELL PROLIF., vol. 43, 2010, pages 207 - 218, XP009153181, DOI: doi:10.1111/j.1365-2184.2010.00675.x
RIPAMONTI U, VAN DEN HEEVER B, CROOKS J, RUEGER DC, REDDI AH: "Long-term evaluation of bone formation by osteogenic protein 1 in the baboon and relative efficacy of bone-derived bone morphogenetic proteins delivered by irradiated xenogeneic collagenous matrices", J BONE MINER RES., vol. 15, 2000, pages 1798 - 809, XP055073962, DOI: doi:10.1359/jbmr.2000.15.9.1798
RIPAMONTI U: "Soluble osteogenic molecular signals and the induction of bone formation", BIOMATERIALS, vol. 27, 2006, pages 807 - 22, XP025097035, DOI: doi:10.1016/j.biomaterials.2005.09.021
SZACHOWICZ EDWARD H: "Facial bone wound healing: An overview", OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA, vol. 28, no. 5, 1995, pages 865 - 880, XP009153246, ISSN: 0030-6665 *
VAN DEN BEUCKEN J J J P ET AL: "In vivo effects of TGF-beta 1-loaded polymeric microsphere incorporation in injectable cap cement", TISSUE ENGINEERING PART A, vol. 14, no. 5, May 2008 (2008-05-01), & ANNUAL TISSUE-ENGINEERING-AND-REGENERATIVE-MEDICINE-INTERNATIONAL-SOC IETY-EUROPEAN-CHAPTER MEETING; OPORTO, PORTUGAL; JUNE 22 -26, 2008, pages 745 - 746, XP009153244, ISSN: 1937-3341 *

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