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Autograft replacements and growth factors

Infuse™ bone graft

<p>Infuse™&nbsp;bone graft (rhBMP-2/ACS) is an autograft replacement that works by stimulating natural bone formation.</p>

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Product details

The mechanism of action and rhBMP-2‡,2

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.3

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 (rh Insulin) is formulated using recombinant techniques as well. This production method offers the advantage of tightly controlled manufacturing processes to ensure purity, consistency, and sterility.

 

Mechanism of action for rhBMP-2/ACS†

1 Implantation rhBMP-2/ACS is implanted.
2 Chemotaxis Mesenchymal stem cells and other bone-forming cells migrate 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.4–8

Step 4: Differentiation

Binding to specific receptors on the surface of the MSC, rhBMP-2 causes them to differentiate into bone-forming cells.3,8 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.4–20

A 2003 in-vitro study compared the bone-forming activity of 14 recombinant human bone morphogenetic proteins.21 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.2

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.2

 

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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.

 

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Kit components

Kit components 7510050 XX small kit 7510100 X small kit 7510200 small kit
Total graft volume 0.7 mL 1.4 mL 2.8 mL
Sterile water for injection (1) 10 mL vial (2) 10 mL vials (1) 10 mL vial
Sterile rhBMP-2 (1) 1.05 mg vial (2) 1.05 mg vials (1) 4.2 mg vial
Sterile absorbable collagen sponge (ACS) (1) ½" x 2" sponge (1) 1" x 2" sponge (2) 1" x 2" sponges

 

Kit components 7510400 medium kit 7510600 large kit 7510800 large II kit
Total graft volume 5.6 mL 8.0 mL 8.0 mL
Sterile water for injection (2) 10 mL vials (1) 10 mL vial (1) mL vial
Sterile rhBMP-2 (2) 4.2 mg vials (1) 12.0 mg vial (1) 12.0 mg vial
Sterile absorbable collagen sponge (ACS) (4) 1" x 2" sponges (6) 1" x 2" sponges (1) 3" x 4" sponges

 

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† 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.

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