BONE GRAFT MATERIAL FOR USE IN A SPINAL FUSION METHOD

Abstract

The invention concerns a bone graft material for use in a spinal fusion method, wherein the material comprises i) a composition for forming a matrix, comprising at least a first matrix material precursor component and a second matrix material precursor component, capable of forming a matrix by crosslinking of the precursor components under appropriate conditions; and ii) a bioactive factor, which is biologically active to stimulate bone formation between two vertebrae, and for effecting or supporting spinal fusion; wherein the spinal fusion method comprises the steps of applying a cage in between the two vertebrae, which is not pre-filled with the bone graft material; and subsequently applying the bone graft material adjacent to and/or into the cage, such that essentially the entire remaining volume between the two vertebrae is filled with the bone graft material. The invention allows for ease of use while forming a more homogeneous matrix.

Claims

1. A bone graft material for use in a spinal fusion method, wherein the material comprises i) a composition for forming a matrix, comprising at least a first matrix material precursor component, and a second matrix material precursor component, capable of forming a matrix by crosslinking of the precursor components under appropriate conditions; and ii) a bioactive factor, which is biologically active to stimulate bone formation between two vertebrae, and for effecting or supporting spinal fusion; wherein the spinal fusion method comprises the steps of applying a cage in between the two vertebrae, which cage is not pre-filled with the bone graft material; and subsequently applying the bone graft material adjacent to the cage and/or into the cage, such that essentially the entire remaining volume between the two vertebrae is filled with the bone graft material.

2. The bone graft material of claim 1, wherein the bioactive factor is suitable to be releasably incorporated in the matrix upon crosslinking of the matrix material precursor components.

3. The bone graft material of claim 1, wherein the bioactive factor is PTH or a biologically active fragment thereof, or a peptide comprising PTH or a biologically active fragment thereof.

4. The bone graft material of claim 3, wherein the peptide is a fusion peptide comprising at least two domains, and wherein the first domain comprises PTH or a biologically active fragment thereof, and the second domain comprises a crosslinkable substrate domain.

5. The bone graft material of claim 4, wherein the crosslinkable substrate domain is or comprises a transglutaminase substrate domain.

6. The bone graft material of claim 4, wherein the fusion peptide comprises an enzymatic or hydrolytic degradation site between the first and the second domain.

7. The bone graft material of claim 1, wherein the matrix is fibrin; and the composition for forming the matrix comprises fibrinogen, thrombin and a calcium source.

8-9. (canceled)

10. A spinal fusion method, comprising the steps of i) providing a cage that is suitable for applying in between two vertebrae; ii) providing a bone graft material for use in a spinal fusion method, wherein the material comprises a. a composition for forming a matrix, comprising at least a first matrix material precursor component, and a second matrix material precursor component, capable of forming a matrix by crosslinking of the precursor components under appropriate conditions; and b. a bioactive factor, which is biologically active to stimulate bone formation between two vertebrae, and for effecting or supporting spinal fusion; iii) applying the cage in between the two vertebrae, which cage is not pre-filled with the bone graft material; and iv) subsequently applying the bone graft material adjacent to the cage and/or into the cage, such that essentially the entire remaining volume between the two vertebrae is filled with the bone graft material.

11. The spinal fusion method of claim 10, wherein the bone graft material is applied in step iv) when between 30 seconds and 420 seconds have lapsed after the first and the second matrix material precursor components have been first brought in contact with each other.

12. The spinal fusion method of claim 10, wherein step iv) is carried out in a time frame of between 5 seconds and 60 seconds.

13. The spinal fusion method of claim 10, wherein the first and the second matrix material precursor components are mixed for about 20 seconds to about 40 seconds after having been first brought in contact with each other.

14. The spinal fusion method of claim 10, wherein the bone graft material is allowed to undergo initial polymerization after mixing and before step iv) for about 20 seconds to about 40 seconds.

15. The spinal fusion method of claim 10, wherein step iv) is carried out before the polymerization of the bone graft material has reached the gel point, preferably at least 0.5 minute, preferably 1.0 minute, further preferably 1.5 minutes, more preferably at least 3 minutes before the graft material has reached the gel point.

16. A kit for use in a spinal fusion method, comprising the bone graft material of claim 1, and instructions for use of the bone graft material in the spinal fusion method of claim 11.

17. The kit of claim 16, further comprising a syringe for containing the bone graft material.

18. The kit of claim 17, further comprising a cannula suitable to be used with the syringe, for delivery of the bone graft material in between the two vertebrae, wherein the cannula has a length of at least 40 mm and an inner diameter of at least 0.51 mm (21G).

19. The kit of claim 16, further comprising a cage that is suitable for applying in between two vertebrae.

Description

[0047] The invention will be described in the following by way of a specific embodiment which is not intended to limit the overall concept of the invention as discussed above in any way.

[0048] FIG. 1A: Schematic illustration of the application of the bone graft material into and next to the previously inserted cage;

[0049] FIG. 1B: Experimental testing of application of the bone graft material using a disc place model; the individual pictures show the bone graft flow at different time points.

PREPARATION OF BONE GRAFT MATERIAL

[0050] The bone graft material consists of a TGplPTH.sub.1-34 peptide solution and a fibrin sealant, as previously disclosed in WO 2012/123028 A1. This bone graft material is prepared on-site immediately prior to use as follows.

In the Non-Sterile Field:

[0051] 1. Thaw the vial of TGplPTH.sub.1-34 solution at ambient conditions.

In the Sterile Field:

[0052] 2. Thaw and warm the ARTISS pre-filled 10 ml syringe according to the preparation instructions described in the prescribing information from Baxter for ARTISS [Fibrin Sealant (Human)]. [0053] 3. Using aseptic transfer technique and a 1 ml syringe, withdraw 0.5 mL of the TGplPTH.sub.1-34 solution (see 1 above), holding up the inverted vial to facilitate withdrawal. [0054] 4. Transfer the complete 0.5 ml volume of TGplPTH.sub.1-34 solution from the 1 ml syringe to a 10 ml syringe, using a female luer to female luer connector.

[0055] After complete thawing and warming of the ARTISS pre-filled 10 ml syringe, remove the cap and connect the nozzles of the double-chamber syringe to the joining piece, ensuring that they are firmly fixed. Secure the joining piece by fastening the tether strap to the double chamber syringe and insert the double plunger. [0056] 5. Using the female luer to female luer connector and connect the ARTISS double chamber syringe with the 10 mL syringe containing the 0.5 mL TGplPTH.sub.1-34 solution.

Immediately Prior to Application of the Bone Graft Material:

[0057] 6. Expel the content from the ARTISS syringe into the 10 mL syringe containing 0.5 mL of the TGplPTH.sub.1-34 solution. Remove the ARTISS double chamber syringe and joining piece from the luer connector and connect an empty 10 mL syringe to the 10 mL syringe containing TGplPTH.sub.1-34 and ARTISS.

[0058] (Step 6 is equal to the start of mixing the constituent parts.) [0059] 7. Mix the TGplPTH.sub.1-34 solution and the ARTISS by transferring the mixture back and forth 5 times between the two syringes. [0060] 8. Remove the empty syringe and the luer connector and connect the syringe containing the bone graft material (TGplPTH.sub.1-34 fibrin sealant) with a cannula (i.e. 14G).

[0061] (Steps 6-8, i.e. the combining and mixing of the TGplPTH1-34 solution and ARTISS lasts approx. 30 seconds.) [0062] 9. Incubate the KUR-113 Bone Graft for at least 30 seconds, to allow initial polymerization of the fibrin gel into a moldable fibrin matrix. [0063] 10. Immediately before application, expel and discard the first several drops from the application cannula.

Application of Bone Graft in Disc Space Modell:

[0064] The disc space model allows to simulate the application of the bone graft material as an adjunctive therapy to hardware in spinal fusion procedures. The model contains a space comparable to the shape and size of cleared disc space and an aperture at the top for the insertion of a spinal implant (‘cage’) and the application of the bone graft material; see FIG. 1B. To monitor the procedure and visually inspect the product, the disc space model was made with a transparent plexiglass pane.

[0065] The application of the bone graft material after an empty spinal implant had been placed in the cleared disc space was studied using the disc space model. Briefly, an empty spinal implant was inserted in the disc space model. Then the aforementioned bone graft material was prepared as described above and injected in the disc space model using a 14 G cannula that was placed adjacent to the inserted spinal implant. As shown in the time lapse images of FIG. 1B, although the cannula was placed next to the inserted spinal implant, upon expelling of the bone graft material, the disc space and the cage are homogenously filled with bone graft. Hence, surprisingly application of the bone graft material adjacent to an inserted spinal implant allows to homogenously fill the spinal implant and disc space with a single application after a spinal implant has already been inserted in the disc space.

[0066] Similar results have been obtained when bone graft material was inserted into the spinal implant instead of the aforementioned procedure (not shown in detail), such that the space between the two vertebrae is filled with the bone graft material flowing from inside of the spinal implant to the outer, remaining space.