COLLAGEN/HYDROXYAPATITE COMPOSITE SCAFFOLD, AND PROCESS FOR THE PRODUCTION THEREOF

• US 20100158976A1
• Filed: 02/11/2008
• Published: 06/24/2010
• Est. Priority Date: 02/09/2007
• Status: Active Grant

• Current Assignee: Royal College of Surgeons in Ireland
• Original Assignee: Royal College of Surgeons in Ireland
• Inventors: Gleeson, John Patrick, Plunkett, Niamh, O'Brien, Fergal Joseph
• Granted Patent: US 8,435,552 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 27/46 with phosphorus-containing inorganic fillers
• CPC Class Codes: A61L 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders

Abstract

A process for producing a collagen/hydroxyapatite (HA) composite scaffold comprises the steps of forming a homogenous suspension of collagen and HA in an acidic solution, lyophilising the suspension until a desired final freezing temperature is reached to produce the composite scaffold, and optionally cross-linking the composite scaffold, wherein the ratio of HA to collagen is at least 1:10 (w/w). Also provided is a collagen/hydroxyapatite (HA) composite scaffold comprising a homogenous distribution of hydroxyapatite within a porous, crosslinked, collagen matrix, wherein the ratio of HA to collagen is at least 1:10 (w/w). Suitably, the composite scaffold has a porosity of at least 99% (v/v), and a compressive stiffness of at least 0.3 KPa. Composite scaffolds of the invention may be used to provide osteoconductive bone implants and tissue engineering implants.

Claims

1-50. -50. (canceled)

51. A process for producing a collagen/hydroxyapatite (HA) composite scaffold, comprising the steps of mechanically mixing collagen and HA in an acidic solution to form a homogenous suspension of collagen and HA in an acidic solution, freezing the suspension at a constant cooling rate until a final freezing temperature of between −

10°

C. and −

70°

C. is reached, and heating the frozen suspension to a sublimation temperature where an ice phase in the frozen suspension is sublimated under vacuum for a suitable period of time to produce the composite scaffold, wherein the ratio of HA to collagen in the suspension is at least 1;

10 (w/w), and the amount of collagen in the suspension is from 3 g/L to 8 g/L (w/w), wherein the homogenous suspension of collagen/HA is formed by the steps of forming an acidic homogenous suspension of collagen, and subsequently adding the HA to the collagen suspension under conditions of mixing to ensure homogenous distribution of the HA within the collagen suspension, in which the HA is added in the form of an acidic HA suspension.

52. A process as claimed in claim 51 in which the acidic suspension HA is added in aliquots.

53. A process as claimed in claim 52 in which the aliquots are added to the collagen suspension at intervals of between 30 and 240 minutes.

54. A process as claimed in claim 51 in which the acidic solution has a molarity of at least 0.1M.

55. A process as claimed in claim 51 in which the ratio of HA to collagen in the suspension is from 1:

10 (w/w) to 50;

10 (w/w).

56. A process as claimed in claim 55 in which the ratio of HA to collagen in the suspension is from 5:

10 to 30;

10 (w/w).

57. A process as claimed in claim 51 in which freezing is carried out at a constant cooling rate of between 0.5°

C./min to 1.5°

C./min.

58. A process as claimed in claim 51 in which the desired final freezing temperature is from −

30°

C. and −

50°

C.

59. A process as claimed in claim 51 further comprising an annealing step that comprises increasing the temperature in the lyophilisation chamber after the final freezing temperature has been reached to an annealing temperature that is intermediate the final freezing temperature and the sublimation temperature, and holding the temperature at the annealing temperature for a period of time before increasing the temperature to the sublimation temperature.

60. A process as claimed in claim 51 in which the HA employed in the present invention is in powder form.

61. A process as claimed in claim 51 in which the collagen employed in the present invention is collagen fibres.

62. A process as claimed in claim 51 in which the composite scaffold is cross-linked by a means selected from the group consisting of:

dehydrothermal cross-linking; and

chemical cross-linking.

63. A collagen/hydroxyapatite (HA) composite scaffold obtainable by the method of claim 51.

64. A collagen/hydroxyapatite (HA) composite scaffold comprising a homogenous distribution of hydroxyapatite within a porous, collagen matrix, wherein the ratio of HA to collagen is at least about 1:

10 (w/w), and wherein composite scaffold has a porosity of at least 95% (v/v) and a compressive stiffness of at least 0.4 KPa.

65. A collagen/hydroxyapatite (HA) composite scaffold as claimed in claim 64 having a homogenous pore size.

66. A collagen/hydroxyapatite (HA) composite scaffold as claimed in claim 65 having a porosity of at least 98% (v/v).

67. A collagen/hydroxyapatite (HA) composite scaffold as claimed in claim 64, which is crosslinked and has a compressive stiffness of at least 1.0 kPa.

68. A collagen/hydroxyapatite (HA) composite scaffold as claimed in claim 64, which is crosslinked and has a compressive stiffness of at least 3.0 kPa.

69. A collagen/hydroxyapatite (HA) composite scaffold as claimed in claim 64 which the composite scaffold is characterised by having a flow conductivity under pressure through the scaffold of at least 1×

10<sup>−

10</sup> m⁴/Ns.

70. A collagen/hydroxyapatite (HA) composite scaffold as claimed in claim 64 for use as an osteoconductive bone implant, a tissue engineering implant, a maxillofacial bone graft substitute, a dental bone graft substitute, a cartilage defect repair implant, or a osteochondral defect repair implant.