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

• US 9,138,483 B2
• Filed: 03/06/2013
• Issued: 09/22/2015
• 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: O'Brien, Fergal Joseph, Gleeson, John Patrick, Plunkett, Niamh
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): CRAIGO, WILLIAM A
• Application Number:
  US13/786,891
• Publication Number:
  US 20130177648A1
• Time in Patent Office: 930 Days
• US Class Current: 1/1
• 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 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 97% (v/v) and a compressive stiffness of at least 0.4 KPa, wherein the composite scaffold further comprising a cell.

2. The collagen/hydroxyapatite (HA) composite scaffold of claim 1, wherein the composite scaffold comprises at least 1×

10⁶ cells per 500 mm³ volume of scaffold.

3. The collagen/hydroxyapatite (HA) composite scaffold of claim 1, wherein the cells are osteoblasts.

4. The collagen/hydroxyapatite (HA) composite scaffold of claim 1, wherein the composite scaffold is characterised by a level of proliferation of MC3T3 osteoblasts in the scaffold at 28 days incubation minus the level at 7 days of at least 0.5×

10⁶ cells.

5. The collagen/hydroxyapatite (HA) composite scaffold of claim 1, wherein the composite 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.

6. The collagen/hydroxyapatite (HA) composite scaffold of claim 1, wherein the composite scaffold has a porosity of at least 97% (v/v).

7. The collagen/hydroxyapatite (HA) composite scaffold of claim 1, wherein the composite scaffold has a homogenous pore size.

8. The collagen/hydroxyapatite (HA) composite scaffold of claim 1, wherein the composite scaffold is cross-linked and has a compressive stiffness of at least 1.0 kPa.

9. The collagen/hydroxyapatite (HA) composite scaffold of claim 1, wherein the scaffold is cross-linked and has a compressive stiffness of at least 3.0 kPa.

10. The collagen/hydroxyapatite (HA) composite scaffold of claim 1, wherein the composite scaffold is characterized by having a flow conductivity under pressure through the scaffold of at least 1×

10<sup>−

10</sup> m⁴/Ns.

11. The collagen/hydroxyapatite (HA) composite scaffold of claim 1, wherein the ratio of HA to collagen ranges from 5:

10 (w/w) to 30;

10 (w/w).

12. The collagen/hydroxyapatite (HA) composite scaffold of claim 1, wherein the ratio of HA to collagen ranges from 10:

10 (w/w) to 30;

10 (w/w).

13. The collagen/hydroxyapatite (HA) composite scaffold of claim 1, wherein the HA is in form of particles.

14. The collagen/hydroxyapatite (HA) composite scaffold of claim 12, wherein HA has a particle size of from 10 nm to 100 μ

m.

15. The collagen/hydroxyapatite (HA) composite scaffold of claim 1, wherein the composite scaffold is obtained by a process 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.