Degenerative Intervertebral Disc Disease
Degenerative intervertebral disc disease is a gradual process in which the intervertebral discs lose their ability to act as an effective shock absorber and become less flexible. It is primarily an age-related disease, but can also be caused by major injuries to the spine. It afflicts nearly half the US population between 40 and 60 years of age and approximately 90% of Americans older than 60.
In its most advanced stages, disc degeneration may be followed by ultimate collapse, producing excruciating pain. In cases of degeneration leading to collapse, most frequently in the cervical or lumbar region, patients suffer from debilitating pain, and impairment of neurological function.
Spinal Fusion using bone grafts
Patients who fail to experience improvement with bed rest and anti-inflammatory medications are often diagnosed with a herniated disc. Treatment for this indication may involve discectomy, or fusion of affected vertebral bodies. Fusion procedures are designed to eliminate motion between the affected vertebrae, thus providing pain relief at the site of spinal instability.
The gold standard surgical procedure for spinal fusion involves fusion of the vertebrae using autogeneous cancellous bone harvested from the iliac crest, with or without pedicle screws, plates or cages. In these cases bone grafts provide osteoconductive scaffolds for local natural bone growth and more rapid fusion results.
Bone graft material may be placed posterolaterally or directly into the intervertebral gap formerly occupied by the degenerated disc and might be placed into a titanium fusion cage, allograft bone dowel, or femoral ring allografts to induce bone growth into, around and through the structure replacing the disc 1.
Problems with autogenous bone trans-plants
Although autogenous bone grafts have so far been viewed as a cost-effective method, hospitals and health insurance funds have increasingly become conscious of the costs associated with surgical intervention and the recovery time for the patient.
For patients, the use of secondary surgery to harvest bone grafts is mostly combined with additional morbidity and post-operative discomfort. In addition, spinal fusion requires a comparatively large amount of bone (up to 40cc per procedure) and it may not be possible to harvest sufficient quantities and bone quality in elderly patients. Consequently, human allografts, xenografts using bovine bone or synthetic biomaterials are used instead.
Although these approaches can stabilise the spine, osteoinduction is limited and fusion therefore takes a considerable time or might even be incomplete.
The use of bone morphogenetic proteins (BMPs) in orthopaedic applications
An alternative approach to autogenous grafts is the use of bone morphogenic proteins (BMPs) to induce bone formation in the region of application. Using BMPs, osteoinduction can be achieved by avoiding secondary surgery, multiple complications and limited biological value due to inconsistent bone quality. The BMP is administered usually with collagen, a soft squeezable biomaterial that can be molded into the cavity to be filled.
However, to ensure it has an appropriate effect, high doses of BMP are required. This has obvious safety implications and the risk of osteoinduction in regions distal to the site of application is greatly enhanced.
Bone morphogenetic proteins in spinal fusion
In spinal surgery, mechanical loading conditions are a major challenge for the biomechanical properties of new artificial bone substitutes. Collagen-mediated applications of BMP are sponge-like in texture and are completely unable to withstand the enormous forces exerted on the spine.
Therefore, they are usually administered in combination with titanium cages that provide the necessary support. The sponge is inserted into the cage device, which is implanted between the degenerated vertebrae to keep the vertebrae properly spaced and aligned during the fusion process.
In a number of preclinical and clinical studies these procedures have been shown to be as effective as autogenous bone graft 2. However, a major drawback of collagen-based material is that very high doses of growth factor are necessary to induce sufficient bone growth across the site of spinal fusion. The bovine origin of the collagen is also a drawback.
The use of ceramic biomaterials in spinal fusion
An alternative to the use of bovine collagen would be to combine the bone morphogenetic protein with a ceramic biomaterial with strong biomechanical properties. There are a number of highly effective ceramic biomaterials with osteoconductive properties used for many years in orthopaedic applications, such as ß-tricalcium phosphate (ß-TCP). ß-TCP is a synthetic calcium-based biomaterial, which acts as a scaffold for new bone ingrowth. As a bone replacement material it has properties ideal for use in spinal fusion. It displays pressure-resistant characteristics and has scaffold properties for cell in-growth (osteoconduction).
Until recently it had proved difficult to find a way of combining bone morphogenetic proteins with ceramic biomaterials as easily as they are combined with the sponge-like collagen. However, we have developed a proprietary coating technology for the non-covalent association of proteins with the surface of ß-TCP-granules (granule size greater than 0,5 mm).
This proprietary coating technology allows for a homogeneous protein coating on the ß-TCP matrix while maintaining the biological activity of the growth factor, avoiding structural modifications as well as aggregation of the protein.
Scil Technology has already successfully demonstrated in various preclinical models, including dental and orthopaedic applications, that this homogeneous coating technology has a dramatic beneficial impact on the biological efficacy of the growth factor 3. This means that lower concentrations of growth factors can be used than in collagen applications while retaining equivalent or superior efficacy and a reduced side-effect profile.
ST01 – a regenerative orthopaedic biomaterial for spinal fusion
Scil Technology is currently developing one such regenerative biomaterial for spinal fusion surgery using this novel coating technology. ST01 is a fully synthetic bone substitute material for lumbar, thoracic and cervical spinal fusion and related procedures. The growth factor is a recombinant human variant of a bone morphogenetic protein 2 (rhBMP-2) manufactured in E. coli. rhBMP-2 is used for effective bone augmentation in orthopaedic indications providing strong osteoinductive properties.
The growth factor is combined with the granular ß-TCP scaffold, which is compression resistant and displays osteoconductive characteristics allowing for cell infiltration and new bone formation. The ß-TCP scaffold degrades over time and ultimately the biomaterial will entirely be replaced by the patient’s own bone.
Preclinical Results
ST01 is currently in the development phase for various indications and will shortly enter the clinical phase for spinal fusion. Highly promising preclinical data have already been obtained in a relevant rabbit spinal fusion model (posterolateral interbody fusion model) showing superior efficacy compared to collagen based rhBMP-2 and autograft. After a healing period of three weeks, histological analysis demonstrated that 150mg rhBMP-2 variant coated on ß-TCP resulted in fusion in 6 out of 7 animals (see table 1) in contrast to 3 out of 6 animals for the collagen/BMP-2 combination.
At the three-week stage no animal treated with autogenous bone graft or ß-TCP alone showed fusion and both demonstrated only immature callus and little neobone formation in the region of administration.
Table 1:
Posterolateral spinal fusion in rabbits (3 weeks observation period)
| Manual
Fused | Histology
Fused | X-ray
Fused | CT
Fused |
| Autograft | 0/6 | 0/6 | 0/5 | 0/3 |
| TCP | 0/6 | 0/5 | 1/6 | 0/5 |
| TCP (30mg BMP2) | 0/7 | 1/6 | 0/6 | n.d. |
| TCP (150mg BMP2) | 4/7 | 6/7 | 3/5 | 4/5 |
| Collagen (150mg BMP2) | 3/6 | 3/6 | 3/5 | 3/5 |
This data indicates that the homogenous rhBMP-2 coated ß-TCP appears to be superior to the current gold standard treatment for spinal fusion, autograft, and that fusion can be achieved with a lower dose of BMP-2 than that used in collagen/BMP-2 combinations. The spacial distribution of new bone formation was highly controlled and the product is considered to be safe.
ST01 will shortly enter clinical trials for spinal fusion. For further information,
www.scil.com/home.htm
References
- Market Dynamics: Bone Substitutes and Growth Factors; Datamonitor, December 2002
- Homepage Medtronic Sofamor Danek, March 2005
- Gruber et. al, Int. Journal of Oral Maxillofac. Implants, in preparation
