Healthcare Professionals

Infuse Bone Graft

Bone Grafting (Spine and Orthopaedic)

  

RECOMBINANT HUMAN BONE MORPHOGENETIC PROTEIN-2 (rhBMP-2)

Infuse™ Bone Graft is the premium product for autograft replacement* due to its high osteoinductivity. Infuse bone graft is recombinant human bone morphogenetic protein-2 (rhBMP-2) applied to an absorbable collagen sponge carrier (ACS). One of the functions of the protein is to stimulate natural bone formation. Overall, bone morphogenetic protein technology has a lengthy history of extensive research and study dating back more than 50 years.

A highly osteoinductive, osteoconductive autograft replacement

THE MECHANISM OF ACTION AND rhBMP-2†1

Bone morphogenetic proteins (BMPs) play a role in the formation of bone and cartilage, the healing of fractures, and the repair of other musculoskeletal tissues.2

The preferred method for obtaining BMP is to manufacture a recombinant version of a naturally occurring BMP using well-established molecular biology techniques. Recombinant human insulin (rhInsulin) is formulated using recombinant techniques as well. This production method results in a pure, single BMP. Recombinant production offers the advantage of tightly controlled manufacturing processes to ensure purity, consistency, and sterility.

The Mechanism of Action (MOA) includes six steps. Table 1 includes an overview of the steps, and each step is described in detail below.

INFUSE BONE GRAFT MOA ANIMATION

See how rhBMP-2 attracts bone-forming cells and generates new bone.
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Table 1: Mechanism of Action for rhBMP-2/ACS*
1 Implantation rhBMP-2/ACS is implanted.
2 Chemotaxis Migration of mesenchymal stem cells and other bone-forming cells to the site of implantation.
3 Proliferation rhBMP-2/ACS provides an environment where stem cells multiply prior to differentiation.
4 Differentiation rhBMP-2 binds to specific receptors on the stem cell surface signaling them to differentiate into osteoblasts.
5 Bone formation and angiogenesis Osteoblasts respond to local mechanical forces to produce new mineralized tissue replacing the ACS. New blood vessel formation is observed at the same time.
6 Remodeling The body continues to remodel bone in response to the local environmental and mechanical forces, resulting in normal trabecular bone.

Step 1: Implantation

When rhBMP-2 is placed on an ACS and implanted in the body, it produces new bone tissue at the site of implantation. Neither the rhBMP-2 nor the ACS can produce new bone tissue independently. Only when they're used together do they initiate the bone induction process.

Step 2: Chemotaxis

Bone-forming cells migrate to the area of the rhBMP-2/ACS implant. This cell migration stimulated by a chemical response is called chemotaxis. Mesenchymal stem cells (MSC) move from bleeding bone, muscle, and the periosteum to infiltrate the implant.

Step 3: Proliferation

The mesenchymal stem cells around the rhBMP-2/ACS implant increase in number. In-vitro studies have shown that rhBMP-2 can increase the proliferation of several multipotent cell lines, which can differentiate into osteoblasts, or bone-forming cells.3-7

Step 4: Differentiation

Binding to specific receptors on the surface of the MSC, rhBMP-2 causes them to differentiate into bone-forming cells.2, 7 In-vitro studies of rhBMP-2 support the fact that differentiation of mesenchymal stem cells into bone-forming osteoblasts plays an essential role in the induction of new bone.1 Pre-clinical studies have shown that rhBMP-2 can cause the differentiation of precursor cells into osteoblasts.3-19

A 2003 in-vitro study compared the bone-forming activity of 14 recombinant human bone morphogenetic proteins.20 Three cell lines, representing the different stages of osteoblast differentiation, were each tested. Alkaline phosphatase activity — a measure of the amount of new bone formation — was significantly increased in all three cell lines by BMP-2, BMP-6, and BMP-9. The researchers concluded that BMP-2, BMP-6, and BMP-9 may be the most potent agents to induce osteoblast lineage-specific differentiation of mesenchymal stem cells.

Step 5: Bone formation

As the sponge degrades or dissolves, these stem cells differentiate into osteoblast and begin to form trabecular bone and/or cartilage. Blood vessel formation (angiogenesis) is observed at the same time. The bone formation process develops from the outside of the rhBMP-2/ACS implant towards the center until the entire implant is replaced by trabecular bone.

Pre-clinical studies support that the bone formation started by rhBMP-2/ACS is self-limiting, forming a predictable amount of bone at the site of implantation. The ability of rhBMP-2 to induce new bone formation depends on its concentration. The rate of bone formation, the amount of bone formed, and the density of the resulting bone are positively correlated with both the concentration of rhBMP-2 and the length of time that rhBMP-2 is present at the implant site.1

Step 6: Remodeling

Remodeling of the trabecular bone induced by rhBMP-2 is consistent with the biomechanical forces placed on it. Radiographic, biomechanical, and histologic evaluation of the induced bone indicates that it functions biologically and biomechanically as native bone. Preclinical studies also indicate that the induced bone can repair itself, if fractured, in a manner indistinguishable from native bone healing.1


MANUFACTURING rhBMP-2

The key element to Infuse bone graft is rhBMP-2 which is manufactured using well-established molecular biology techniques. This protein is a replication of bone morphogenetic protein-2 (BMP-2), which occurs naturally in humans and is important in healing and regenerating bone. This tightly controlled process of manufacturing rhBMP-2 ensures consistency and sterility of pure solutions of BMP. The process includes two phases.

PHASE 1: IDENTIFYING, REPLICATING, AND STORING THE HUMAN GENE FOR BMP-2

The process began by first identifying and isolating the specific gene that carries the code for making bone morphogenetic protein-2. Once it was isolated, it was spliced and then recombined into the DNA of a commonly used mammalian cell, called a production cell. Recombinant refers to the insertion, or recombination, of the gene into the production cell.

As these recombined cells grow and multiply, they include the new gene in their DNA. This replication process results in a homogeneous population of cells that can produce rhBMP-2.

A single batch of rhBMP-2 production cells is grown and distributed into several hundred small vials, called a cell bank. This bank is the source for all future production of rhBMP-2. To safely maintain the cells, the small vials are frozen at -135°C and stored in secure, monitored, temperature-controlled freezers. Because only a few recombined cells are needed to make many millions of rhBMP-2 units and future cell banks, the isolation and cloning process doesn't need to be repeated.

PHASE 2: PRODUCING, PURIFYING, AND STERILIZING rhBMP-2

To produce rhBMP-2, a vial of the production cells is placed into a glass spinner flask. This flask contains nutrients the cells need to grow and produce rhBMP-2. These nutrients, or "medium," contain a combination of vitamins, amino acids, minerals, and sugar, but they do not contain any human or animal components.

Next, the cells are transferred to a bioreactor, which is a computer-controlled, closed-system environment where large-scale production begins. After a growth period of about three days, the recombined cells are filtered away from the rhBMP-2 containing medium and discarded. The rhBMP-2 moves on to the purification process, which involves a series of four chromatography columns. Then it's sterilized with nano filtration as an added viral safety assurance, even though no human or animal components are added during the recombinant production process.

QUALITY VALIDATION OF rhBMP-2

Throughout the production process, quality control testing is done to assess the safety, consistency, and purity of all materials. This includes a large number of tests that are completed during the manufacture of rhBMP-2. Quality-checked liquid rhBMP-2 is filtered and freeze-dried in vials and then further tested for purity and consistency.


INFUSE BONE GRAFT KIT COMPONENTS

Part numbers and sizes of each component of the Infuse Bone Graft kit.

SMART STORAGE COMPATIBLE

An RFID-based, near real-time tissue tracking system

 

The Smartstorage™ System is an RFID-based, near real-time tissue tracking system that streamlines inventory management. No more worrying about manual recordkeeping — the Smartstorage System keeps accurate usage history and temperature logs. The system also notifies you when conditions need to be checked and assures precise accountability.


MANUALS AND TECHNICAL GUIDES

Find these technical manuals in the Medtronic Manual Library, in the product labeling supplied with each product, or by calling Medtronic at 800-961-9055.


SPINAL INDICATIONS

BRIEF SUMMARY OF INDICATIONS, CONTRAINDICATIONS, AND WARNINGS FOR:
Infuse™ Bone Graft/LT-Cage™ Lumbar Tapered Fusion Device
Infuse™ Bone Graft/Inter Fix™ Threaded Fusion Device
Infuse™ Bone Graft/Inter Fix™ RP Threaded Fusion Device
Infuse™ Bone Graft/Perimeter™ Interbody Fusion Device
Infuse™ Bone Graft/Clydesdale™ Spinal System
Infuse™ Bone Graft/Divergence-L™ Anterior/Oblique Lumbar Fusion System
Infuse™ Bone Graft/Pivox™ Oblique Lateral Spinal System

The Infuse™ Bone Graft/Medtronic Interbody Fusion Device is indicated for spinal fusion procedures in skeletally mature patients with degenerative disc disease (DDD) at one level from L2-S1, who may also have up to Grade I spondylolisthesis or Grade 1 retrolisthesis at the involved level.

The following interbody devices and surgical approaches may be used with Infuse™ Bone Graft:

  • The LT-Cage™ Lumbar Tapered Fusion Device, implanted via an anterior open or an anterior laparoscopic approach at a single level.
  • The Inter Fix™ or Inter Fix™ RP Threaded Fusion Device, implanted via an anterior open approach at a single level.
  • The Perimeter™ Interbody Fusion Device implanted via a retroperitoneal anterior lumbar interbody fusion (ALIF) at a single level from L2-S1 or an oblique lateral interbody fusion (OLIF) approach at a single level from L5-S1.
  • The Clydesdale™ Spinal System, implanted via an OLIF approach at a single level from L2-L5.
  • The Divergence-L™ Anterior/Oblique Lumbar Fusion System interbody device implanted via an ALIF approach at a single level from L2-S1 or an OLIF approach at a single level from L5-S1.
  • The Pivox™ Oblique Lateral Spinal System implanted via an OLIF approach at a single-level from L2-L5.

The Infuse™ Bone Graft/Medtronic Interbody Fusion Device consists of two components containing three parts – a spinal fusion cage, a recombinant human bone morphogenetic protein, and a carrier/scaffold for the bone morphogenetic protein and resulting bone. These components must be used as a system for the prescribed indication described above. The bone morphogenetic protein solution component must not be used without the carrier/scaffold component or with a carrier/scaffold component different from the one described in this document. The Infuse™ Bone Graft component must not be used without the Medtronic Interbody Fusion Device component.

NOTE: The Inter Fix™ Threaded Fusion Device and the Inter Fix™ RP Threaded Fusion Device may be used together to treat a spinal level. The LT-Cage™ Lumbar Tapered Fusion Device, the Perimeter™ Interbody Fusion Device, the Clydesdale™ Spinal System, the Divergence-L™ Anterior/Oblique Lumbar Fusion System, and the Pivox™ Oblique Lateral Spinal System implants are not to be used in conjunction with either the Inter Fix™ OR Inter Fix™ RP implants to treat a spinal level.

The Infuse™ Bone Graft/Medtronic Interbody Fusion Device is contraindicated for patients with a known hypersensitivity to recombinant human Bone Morphogenetic Protein-2, bovine Type I collagen, or to other components of the formulation and should not be used in the vicinity of a resected or extant tumor, in patients with any active malignancy, or patients undergoing treatment for a malignancy; in patients who are skeletally immature; in pregnant women; or in patients with an active infection at the operative site or with an allergy to titanium, titanium alloy, or polyetheretherketone (PEEK).

There are no adequate and well-controlled studies in human pregnant women. In an experimental rabbit study, rhBMP-2 has been shown to elicit antibodies that are capable of crossing the placenta. Women of child bearing potential should be warned by their surgeon of potential risk to a fetus and informed of other possible orthopedic treatments. The safety and effectiveness of this device has not been established in nursing mothers. Women of child- bearing potential should be advised to not become pregnant for one year following treatment with this device.

Please see the Infuse™ Bone Graft package insert for the complete list of indications, warnings, precautions, adverse events, clinical results, definition of DDD, and other important medical information. The package insert also matches the sizes of those sized devices that are indicated for use with the appropriate Infuse™ Bone Graft kit. An electronic version of the package insert may be found at www.medtronic.com/manuals.

CAUTION: Federal (USA) law restricts this device to sale by or on the order of a physician with appropriate training or experience.

TIBIA TRAUMA INDICATIONS

BRIEF SUMMARY OF INDICATIONS, CONTRAINDICATIONS, AND WARNINGS FOR:
INFUSE™ BONE GRAFT

Infuse Bone Graft is indicated for treating acute, open tibial shaft fractures that have been stabilized with IM nail fixation after appropriate wound management. Infuse Bone Graft must be applied within 14 days after the initial fracture. Prospective patients should be skeletally mature.

Infuse Bone Graft consists of two components – recombinant human Bone Morphogenetic Protein-2 solution and a carrier/scaffold for the bone morphogenetic protein solution and resulting bone. These components must be used as a system. The bone morphogenetic protein solution component must not be used without the carrier/scaffold component or with a carrier/scaffold component different from the one described in this document.

Infuse Bone Graft is contraindicated for patients with a known hypersensitivity to recombinant human Bone Morphogenetic Protein-2, bovine Type I collagen or to other components of the formulation and should not be used in the vicinity of a resected or extant tumor, in patients with an active malignancy or patients undergoing treatment for a malignancy. Infuse Bone Graft should also not be used in patients who are skeletally immature, in patients with an inadequate neurovascular status, in patients with compartment syndrome of the affected limb, in pregnant women, or in patients with an active infection at the operative site.

There are no adequate and well controlled studies in human pregnant women. In an experimental rabbit study, rhBMP-2 has been shown to elicit antibodies that are capable of crossing the placenta. Women of child bearing potential should be warned by their surgeon of potential risk to a fetus and informed of other possible orthopedic treatments. The safety and effectiveness of this device has not been established in nursing mothers. Women of child-bearing potential should be advised to not become pregnant for one year following treatment with this device.

Please see the package insert for the complete list of indications, warnings, precautions, adverse events, clinical results, and other important medical information.

CAUTION: Federal (USA) law restricts this device to sale by or on the order of a physician with appropriate training or experience.


*

Approved for use in certain spinal, dental, and trauma indications.

The commonly accepted mechanism of action as determined by in-vitro and in-vivo studies.


1

U.S. Food and Drug Administration. Summary of Safety and Effectiveness Data for Infuse Bone Graft/LT-Cage™ Lumbar Tapered Fusion Device (PMA Number P000058). Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf/p000058b.pdf. Accessed March 10, 2006.

2

Schmitt JM, Hwang K, Winn SR, Hollinger JO. Bone morphogenetic proteins: an update on basic biology and clinical relevance. J Orthop Res. 1999 Mar;17(2):269-278. Review.

3

Yamaguchi A, Katagiri T, Ikeda T, Wozney JM, Rosen V, Wang EA, Kahn AJ, Suda T, Yoshiki S. Recombinant human bone morphogenetic protein-2 stimulates osteoblastic maturation and inhibits myogenic differentiation in vitro. J Cell Biol. 1991 May;113(3):681-687.

4

Puleo DA. Dependence of mesenchymal cell responses on duration of exposure to bone morphogenetic protein-2 in vitro. J Cell Physiol. 1997 Oct;173(1):93-101.

5

Wilke A, Traub F, Kienapfel H, Griss P. Cell differentiation under the influence of rh-BMP-2. Biochem Biophys Res Commun. 2001 Jun 29;284(5):1093-1097.

6

Katagiri T, Yamaguchi A, Ikeda T, Yoshiki S, Wozney JM, Rosen V, Wang EA, Tanaka H, Omura S, Suda T. The non-osteogenic mouse pluripotent cell line, C3H10T1/2, is induced to differentiate into osteoblastic cells by recombinant human bone morphogenetic protein-2. Biochem Biophys Res Commun. 1990 Oct 15;172(1):295-299.

7

Bain G, Muller T, Wang X, Papkoff J. Activated beta-catenin induces osteoblast differentiation of C3H10T1/2 cells and participates in BMP2 mediated signal transduction. Biochem Biophys Res Commun. 2003 Jan 31;301(1):84-91.

8

Kawasaki K, Aihara M, Honmo J, Sakurai S, Fujimaki Y, Sakamoto K, Fujimaki E, Wozney JM, Yamaguchi A. Effects of recombinant human bone morphogenetic protein-2 on differentiation of cells isolated from human bone, muscle, and skin. Bone. 1998 Sep;23(3):223-231.

9

Gallea S, Lallemand F, Atfi A, Rawadi G, Ramez V, Spinella-Jaegle S, Kawai S, Faucheu C, Huet L, Baron R, Roman-Roman S. Activation of mitogen-activated protein kinase cascades is involved in regulation of bone morphogenetic protein-2-induced osteoblast differentiation in pluripotent C2C12 cells. Bone. 2001 May;28(5):491-498.

10

Hughes FJ, Collyer J, Stanfield M, Goodman SA. The effects of bone morphogenetic protein-2, -4, and -6 on differentiation of rat osteoblast cells in vitro. Endocrinology. 1995 Jun;136(6):2671-2677.

11

Boden SD, McCuaig K, Hair G, Racine M, Titus L, Wozney JM, Nanes MS. Differential effects and glucocorticoid potentiation of bone morphogenetic protein action during rat osteoblast differentiation in vitro. Endocrinology. 1996 Aug;137(8):3401-3407.

12

Thies RS, Bauduy M, Ashton BA, Kurtzberg L, Wozney JM, Rosen V. Recombinant human bone morphogenetic protein-2 induces osteoblastic differentiation in W-20-17 stromal cells. Endocrinology. 1992 Mar;130(3):1318-1324.

13

Yamaguchi A, Ishizuya T, Kintou N, Wada Y, Katagiri T, Wozney JM, Rosen V, Yoshiki S. Effects of BMP-2, BMP-4, and BMP-6 on osteoblastic differentiation of bone marrow-derived stromal cell lines, ST2 and MC3T3-G2/PA6. Biochem Biophys Res Commun. 1996 Mar 18;220(2):366-371.

14

Ikeuchi M, Dohi Y, Horiuchi K, Ohgushi H, Noshi T, Yoshikawa T, Yamamoto K, Sugimura M. Recombinant human bone morphogenetic protein-2 promotes osteogenesis within a  telopeptide type I collagen solution by combination with rat cultured marrow cells. J Biomed Mater Res. 2002 Apr;60(1):61-69.

15

van den Dolder J, de Ruijter AJ, Spauwen PH, Jansen JA. Observations on the effect of BMP-2 on rat bone marrow cells cultured on titanium substrates of different roughness. Biomaterials. 2003 May;24(11):1853-1860.

16

Arpornmaeklong P, Kochel M, Depprich R, Kubler NR, Wurzler KK. Influence of platelet-rich plasma (PRP) on osteogenic differentiation of rat bone marrow stromal cells. An in vitro study. Int J Oral Maxillofac Surg. 2004 Jan;33(1):60-70.

17

Fromigue O, Marie PJ, Lomri A. Bone morphogenetic protein-2 and transforming growth factor-beta2 interact to modulate human bone marrow stromal cell proliferation and differentiation. J Cell Biochem. 1998 Mar 15;68(4):411-426.

18

Kim KJ, Itoh T, Kotake S. Effects of recombinant human bone morphogenetic protein-2 on human bone marrow cells cultured with various biomaterials. J Biomed Mater Res. 1997 Jun 5;35(3):279-285.

19

Lecanda F, Avioli LV, Cheng SL. Regulation of bone matrix protein expression and induction of differentiation of human osteoblasts and human bone marrow stromal cells by bone morphogenetic protein-2. J Cell Biochem. 1997 Dec 1;67(3):386-396.

20

Cheng H, et al, Osteogenic Activity of the Fourteen Types of Human Bone Morphogenetic Proteins (BMPs). Journal of Bone and Joint Surgery, 2003, 1544-1552.