Collagen/hydroxyapatite composite scaffold, and process for the production thereof

• US 8,435,552 B2
• Filed: 02/11/2008
• Issued: 05/07/2013
• 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
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): CRAIGO, WILLIAM A
• Application Number:
  US12/526,353
• Publication Number:
  US 20100158976A1
• Time in Patent Office: 1,912 Days
• Field of Search: None
• 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, lyophilizing 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. 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 ranges from 1;

10 (w/w) to 50;

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.

2. A process as claimed in claim 1 in which the acidic suspension HA is added in aliquots.

3. A process as claimed in claim 2 in which the aliquots are added to the collagen suspension at intervals of between 30 and 240 minutes.

4. A process as claimed in claim 1 in which the acidic solution has a molarity of at least 0.1M.

5. A process as claimed in claim 1 in which the ratio of HA to collagen in the suspension is from 5:

10 to 30;

10 (w/w).

6. A process as claimed in claim 1 in which freezing is carried out at a constant cooling rate of between 0.5°

C./min to 1.5°

C./min.

7. A process as claimed in claim 1 in which the desired final freezing temperature is from −

30°

C. and −

50°

C.

8. A process as claimed in claim 1 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.

9. A process as claimed in claim 1 in which the HA employed in the present invention is in powder form.

10. A process as claimed in claim 1 in which the collagen employed in the present invention is collagen fibers.

11. A process as claimed in claim 1 in which the composite scaffold is cross-linked by a means selected from the group consisting of:

dehydrothermal cross-linking; and

chemical cross-linking.

12. A collagen/hydroxyapatite (HA) composite scaffold obtained by the method of claim 1.

21. The process of claim 9, wherein HA has a particle size of from 10 nm to 100 μ

m.

22. The process of claim 5, wherein the ratio of HA to collagen in the suspension ranges from 10:

10 (w/w) to 30;

10 (w/w).

13. A collagen/hydroxyapatite (HA) composite scaffold comprising a homogenous distribution of hydroxyapatite within a porous, collagen matrix, wherein the ratio of HA to collagen ranges from 1:

10 (w/w) to 50;

10 (w/w), and wherein composite scaffold has a porosity of at least 98% (v/v) and a compressive stiffness of at least 0.4 KPa.

14. A collagen/hydroxyapatite (HA) composite scaffold as claimed in claim 13 having a homogenous pore size.

15. A collagen/hydroxyapatite (HA) composite scaffold as claimed in claim 13, which is crosslinked and has a compressive stiffness of at least 1.0 kPa.

16. A collagen/hydroxyapatite (HA) composite scaffold as claimed in claim 13, which is crosslinked and has a compressive stiffness of at least 3.0 kPa.

17. A collagen/hydroxyapatite (HA) composite scaffold as claimed in claim 13 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.

18. The collagen/hydroxyapatite (HA) composite scaffold of claim 13, wherein the collagen scaffold is selected from the group consisting of:

an osteoconductive bone implant, a tissue engineering implant, a maxillofacial bone graft substitute, a dental bone graft substitute, a cartilage defect repair implant, and a osteochondral defect repair implant.

19. The collagen/hydroxyapatite (HA) composite scaffold of claim 13, wherein the ratio of HA to collagen ranges from 5:

10 (w/w) to 30;

10 (w/w).

20. The collagen/hydroxyapatite (HA) composite scaffold of claim 19, wherein the ratio of HA to collagen ranges from 10:

10 (w/w) to 30;

10 (w/w).