Primary spinal cord injury is followed by secondary, biochemical, immunological, cellular changes in the injured cord

A review article written by Brian Kwon looking critically at the use of hypothermia for SCI. It shows that it is neuroprotective in some settings (i.e. cardiac arrest). However, there are 25 animal studies with mixed results and only eight human SCI studies. Importantly, they are all case series of local, not systemic hypothermia. And the last one published was in 1984.

Rho is a critical molecule in SCI. Rho ultimately inhibits axonal growth cone proliferation. Stopping RHO therefore will promote the growth cone. There are two drugs that ultimately targets rho. These are anti nogo antibodies and cethrin both of which ultimately inhibit rho.

President Obama lifted the ban on federal funding of stem cell research. This was a monumental occasion and was right around the time that the FDA approved the first trial of hESC for SCI.

The FDA trial of Geron is with Thoracic ASIA A SCI patients with transplantation of ESC directly into the cord at 7 to 14 days after injury. Geron has provided evidence to the FDA that there is no teratoma formation with transplantation of a human ESC to a rat or mouse. However, we do not know what will happen in a human to human transplant.

In conclusion, use of steroids in setting of SCI is diminishing. There is no clinical evidence to support use of systemic hypothermia. Current clinical trials of pharmacologic therapy include Minocycline and RILUTEK(r) (riluzole) for neuroprotection, Anti-Nogo Antibodies and Cethrin(r) for axonal growth by ultimately inhibiting Rho. There is only one small study supporting safety, not efficacy of OEC transplantation.

Cahill et. al. published a large review of the use of BMP in spinal fusions. They reviewed the nationwide inpatient database, which represents approximately 25% of use U.S. Community Hospitals from the years 2002 to 2006. This included over 300,000 fusion type procedures. They noted increased complications with the use of anterior cervical procedures specifically increased complications with increased dysphasia and wound complications.

Due to these concerns, the Food and Drug Administration released last year a public health notification about the potential life threatening complications related to the use of BMP in anterior cervical spine fusions. Joseph & Rampersaud noticed a 20% incidence of heterotopic ossification in patients undergoing this procedure versus only 8% for patients who had undergone fusions without BMP.

Wong et. al. published a report on five cases of neurologic injury that relate to the use of BMP and the formation of heterotopic bone. Again, the suggestion of a barrier or closure defect was brought up and this may help minimise the risks; however, further work is noted. Multiple authors have noted a phenomenon of osteolysis occurring around graft fusion sites for the use of BMP. McCullen et. al. evaluated that 32 levels in 26 patients who had undergone a TLIF procedure. It is unclear the carcinogenic and tetraogenic effects of the use of BMP in the spine and also, the effects of repeat exposures on BMP has yet to be addressed. Finally, the long term cost and benefits of the use of BMP on the health care system has yet to be fully addressed.

So in conclusion, BMP2 is effective in producing fusions especially in challenging environments, deformity, smoking and infection. However, the complications continue to be a concern especially with regards to interbody fusions as well as in the cervical spine.

Purpose: The decision of whether or not an injury to the sub-axial cervical spine needs operative management often hinges on the stability of the spine. The posterior Ligamentous Complex (PLC) is one of the primary soft tissue stabilizers of the cervical spine. Fat-saturated T2-wieghted MRI sequences are able to demonstrate soft tissue injury to the cervical spine. No studies to date have assessed the ability of MRI to accurately and reliably demonstrate PLC disruption in the sub-axial cervical spine.

Method: Forty-nine consecutive patients aged 14–85 years presenting to the two participating institutions with injury between C3 and T1 who required posterior surgery as part of their management were prospectively enrolled in the study. All patients had radiographs, CT, and MRI scans preoperatively, which were reviewed by a Neuroradiologist, and the treating surgeon separately. Their posterior intraoperative findings were then recorded by the treating surgeon and his assistant. Statistical analysis included Spearman’s rank order correlation, and Cohen’s kappa score.

Results: There was a moderate level of agreement between the radiologist’s interpretation of the preopera-tive MRI and the surgeon’s intraoperative findings for the supraspinous and intraspinous ligaments, (kappa.49 & .48 respectively). A fair level of agreement was found for the ligamentum flavum, left and right facet capsules, and the cervical fascia (kappa scores.31,.30,.30,.39 respectively).

Conclusion: MRI has a high sensitivity (78.6% to 100%) for detecting cervical PLC injury but a low specificity (53.6% to 75%). On its own MRI is not a useful tool for diagnosing cervical spine PLC injury. The clinician should be aware of the relatively high rate of false positive PLC injury diagnosis with MRI.

Injuries of the cervical spine can be classified into six categories according to a mechanistic system describing the biomechanical deficiencies incurred in a cervical spine injury. However high velocity flexion compression loads cause multiple contiguous and noncontiguous fractures due to multiple force vectors. A universal classification system cannot be applied.

Instability exists if there is greater than 3.5 mm of translation or greater than 11 degrees of angulation as compared to other segments. The degree of ligamentous injury on MRI correlates with instability in patients with lateral mass facet fractures, with rupture of multiple ligaments including the anterior longitudinal, posterior longitudinal, interspinous, or facet capsule. Patients with less than 13 mm of narrowing of the sagittal canal are predisposed to neurologic injury. Vertical compression injuries cause canal occlusion and vertebral column shortening. The timing of surgery in cases of spinal cord injury is controversial. There is no difference in outcome between early (< 72 hours) and late (> 5 days) surgery. However, there remains at least a theoretical benefit to early surgery.

Compression-flexion injuries result in loss of the anterior column by compression followed by the posterior column in distraction. The injury is considered unstable if there is a vertical cleavage fracture of the vertebral body or displacement. Treatment includes a cervical orthosis or halo for minor injuries, depending on the degree of kyphosis. Major injuries with displacement should be treated surgically by anterior corpectomy and plate or an anterior/posterior fusion, depending on the degree of posterior instability.

The most common level of vertical-compression injuries is at the C6 or C7 level. Minimally displaced injuries can be treated with a collar or halo. Fragmentation and peripheral displacement of the bony fragments needs a halo followed by surgery and this may include an anterior corpectomy and plating.

Distraction-flexion injuries may result in facet sub-luxation with less than 25% displacement, or dislocation of one (UFD) or both (BFD) facet joints. When there is 3 mm of translation (25%), the canal is occluded 20–25%. With 6mm of translation (50%), there is 40–50% canal occlusion. MRI can help analyse the soft tissue and ligamentous injuries. In UFD, all posterior ligamentous structures including joint capsule, and half the disc annulus are disrupted. Disruption of ALL and PLL is not necessary to create a UFD. In addition to the posterior structures, the ALL, the PLL and disc are disrupted in BFD. Rupture of the intervertebral disc may include posterior herniation or circumferential disruption. All distraction flexion injuries should be reduced closed. The necessity of a preoperative MRI is undetermined. Preoperative MRI is recommended if there is an unreliable exam due to the patient being uncooperative, if there is neurological worsening with, or failure of closed reduction. If the patient is neurologically intact and closed reduction successful, a posterior cervical fusion is advocated if there is no evidence of an extruded disc on the post reduction MRI. If the closed reduction failed, or MRI indicated, and there is no evidence of a herniated disc, an open posterior reduction followed by fusion is performed. Anterior discectomy with reduction, a graft and a plate is performed for a herniated disc.

Compression-extension injuries fail by compression of the posterior elements followed by distraction of the anterior elements. There are unilateral or bilateral fractures of the laminae/neural arch with degrees of displacement. Undisplaced neural arch fractures can be treated with a cervical orthosis or halo. Displaced neural arch fractures are treated with a posterior cervical fusion.

There are two stages in the distraction-extension injury group. The anterior longitudinal ligament is disrupted with possibly a transverse fracture of the body. With more major injuries, there is a significant displacement injuring the posterior column. Stage 1 injuries can be treated with a halo and Stage 2 with an anterior decompression and fusion with a plating device. There are two stages to lateral flexion injuries. Minor injuries include asymmetric centrum fracture and a unilateral arch fracture. In addition, there is displacement of the body with contralateral ligamentous failure in major injuries. The treatment for Stage 1 is usually a collar while treatment for Stage 2 is usually a posterior cervical fusion.

Posterior stabilization procedures may be performed with wires and cables with or without rods. Posterior clamps usually are not recommended; while plates and screws are preferred. The plates and screws are biomechanically superior to wiring and avoid canal penetration. They are ideal when there is loss of the posterior elements. Pedicle fixation should be considered when operating on the C2 or C7 level.

One in five patients may have complete disruption of vertebral artery blood flow. This occurs most commonly with flexion-distraction or flexion-compression injuries. Vertebral artery evaluation is recommended in patients with flexion injuries and symptoms consistent with vertebral artery insufficiency.

It is important to understand the mechanism of injury; to understand which elements are compromised. We have to get the appropriate imaging studies, we have to be cognizant of the fact that the vertebral artery may be injured, or there may be an associated herniated disc. We have to understand the degree of instability, which dictates the appropriate treatment and we have to understand the risk benefit of the specific internal fixation systems that we use.

Arthrodesis of the spine is the preferred surgical treatment for a number of pathological disorders. This process is dependent on three primary components: osteogenic cells with osteoblastic potential, osteoinductive growth factors and an osteoconductive scaffold that facilitates bone formation and vascular ingrowth. Several systemic and local factors are known to affect the rate of spinal fusion. Autogenous bone graft remains the gold standard graft material for spinal fusion. It is the only graft material that supplies the three primary components necessary for a solid fusion. Unfortunately autogenous bone is only available in limited quantities and the procurement of autograft is associated with significant donor site morbidity. A number of different bone graft materials have been developed as alternatives to autograft. These materials may be classified into two major groups, bone graft extenders used to augment autograft, or bone graft substitutes. Several different bone graft materials have been developed including allograft, osteoconductive matrices, demineralised bone matrices, bone marrow aspiration, autologous platelet concentration, growth factors and gene therapy.

Allograft is currently the most widely used substitute for autogenous bone. Because any osteogenic cells are eradicated during the tissue processes, allograft is primary osteoinductive with minimal osteoinductive potential. Processing may affects the structural and biological characteristics of a graft. The incorporation of allograft occurs by a process similar to that observed with autograft but more slowly and is less complete.

Osteoconductive scaffolds do not contain any osteogenic cells or osteoinductive factors and are used as a composite graft as a carrier for either osteogenic cells or osteoinductive growth factors. They are biocompatible and do not illicit a response. There is also no inherent risk of infection and availability is unlimited. These materials are brittle with poor mechanical properties and need to be protected from excessive biomechanical forces until fully incorporated. A number of osteoconductive scaffolds have been developed including ceramics, calcium sulfate, mineralized collagen, bioactive glasses, and porous metals.

Dematerialized bone matrices (DMPs) are osteoinductive with variable osteoconductive properties. DMPs consist of Type I collagen and non-collagenous proteins including multiple signaling proteins. The osteoinductive activity of DMPs is due to a small fraction of bone morphogenic proteins. There is significant variability in the osteoinductive potentials and clinical efficacy of DBMs. DBMs are most effective when combined with autograft or bone marrow aspirate.

Bone marrow aspiration provides osteogenetic cells and osteoinductive growth factors but must be combined with an osteoconductive carrier to form a composite graft. It is associated with minimal morbidity compared to the use of autograft and is easily obtained. Unfractionated bone marrow contains only moderate osteogenic potential. Selective retention technology can increase the number of osteogenic cells then combined with an osteoconductive carrier such as a collagen sponge or DBM.

Activated platelets release multiple factors that may enhance bone formation by promoting chemotaxis, cellular proliferation and differentiation of stem cells. Platelets do not release BMPs so this autologous platelet concentrate is not inductive. Concentrated platelet rich plasma gel is combined with an osteoconductive scaffold or osteogenic cells to form a composite graft for implantation. The capacity for fusion by this technique may be inferior to autologous graft.

Bone morphogenetic proteins are low molecular weight proteins related to the transforming growth factor beta superfamily. They bind receptors on the surface of osteoprogenitor stem cells and activate intracellular signal transduction cascades resulting in the osteoblastic differentiation of pluripotential stem cells. Recombinant BMPs are typically combined with an osteoconductive carrier to form a composite graft. Recombinant BMPs have been used successfully in spinal fusions and may be superior to autograft.

Gene therapy involves the transfer of specific DNA sequence into target cells that express the protein of interest. Gene therapy may provide a more potent osteoinductive signal than recombinant growth factors because the sustained local release of osteogentic proteins may be more physiologic than the administration of a single large dose of recombinant factors. There are potential safety concerns and economic issues.

Autogenous bone remains the gold standard of graft material; however composite grafts consisting of multiple materials may prove to be efficacious for stimulating a spinal fusion.

The most appropriate classification of traumatic thoracolumbar (TL) spine injuries remains controversial and current systems can be cumbersome and difficult to apply. No classification aids decision making in clinical management. Clinical spine trauma specialists from institutions around the world were canvassed with respect to information deemed pivotal in the communication of TL spine trauma and the clinical decision making process. Traditional injury patterns were reviewed and reconsidered in light of these essential characteristics. The reliability and validity of an earlier version of this system has been demonstrated.

The Thoracolumbar Injury Classification and Severity Score (TLICS) was devised based upon the three most important injury characteristics: 1) morphology of injury determined by radiographic appearance, 2) integrity of the posterior ligamentous complex, and 3) neurological status of the patient. These characteristics are largely independent of each other. A composite injury severity score can be calculated from these characteristics stratifying patients into surgical and non-surgical treatment groups. The three principal injury patterns are compression (including burst – 1 point each), translation/rotation (3 points) and distraction (4 points). Neurological status can be classified as a nerve root injury (1 point), a complete (ASIA A-2 points) or incomplete injury (3 points) to the spinal cord or conus, or injury of the cauda equina (3 points). Disruption of the posterior ligamentous complex and facet joint capsules results in instability. Disrupted posterior ligaments can be seen as subluxation or dislocation of a facet, interspinous widening, or MRI evidence of ligament discontinuity. Failure of the posterior ligamentous complex can be classified as indeterminate (2 points) or definitely disrupted (3points).

Coexisting clinical factors (qualifiers) may alter decision making by virtue of their effect on stability, general management or effect on healing. Metabolic disorders such as ankylosing spondylitis, DISH, osteoporosis and age may influence treatment. Injury characteristics such as excessive kyphosis, severe vertebral body collapse and sternal fracture may influence outcome and modify treatment. Treatment options might be influenced in patients with head injuries or polytrauma. The impact of these clinical qualifiers on patient care must be evaluated.

Once all the major variables have been assigned points, a total TLICS Score can be determined. Patients with 3 or less points are non-operative candidates while patients scoring 5 or more points should be considered for surgery. Clinical qualifiers may modify treatment. The morphology of the injury, neurological status, and integrity of the posterior ligamentous complex can help guide the management of TL injuries. Incomplete neurological injuries warrant anterior decompression if posterior realignment is ineffective in relieving neurological compromise. Distraction and translational injuries, and disruptions of the posterior ligamentous complex are managed optimally with an initial posterior approach for realignment and stabilization. Although there will always be limitations to any cataloging system, the TLICSS reflects accepted features cited in the literature important in predicting spinal stability, future deformity, and progressive neurological compromise. This classification system is intended to be easy to apply and to facilitate clinical decision making.

The basis of back pain and disc degeneration is little understood. The end point of disk degeneration is cellular decline, loss of water content, decrease of proteoglycans, decrease in Type II collagen with consequent increase in Type I collagen as well as anular fissures, loss of mechanical competence of the disk facet complex as well as bony changes. Little is known of the process from the healthy disk to more degenerated disc.

The current solution to what is thought to be the causes of the problem is surgery involving disc excision, fusion and/or replacement. These solutions may be the cause of more problems. Frequently these solutions are temporary. The question is whether there is a better or different way to treat this pain-generating disc degeneration. In intervening with disc degeneration by manipulating the cellular environment, timing may be everything. However we do not know at which time point the decline of disc tissue becomes irreversible, when any cellular, genetic or growth factor therapies to try to regenerate will be futile. The goal is to find this point and try to perform therapies that are appropriate at that time point. The strategies should include promoting and upgrading matrix synthesis within the disc, inhibiting the catabolic processes that may be a normal aging process, and to try to replace the loss number of cells to increase the matrix to avoid the imbalance between synthesis and catabolism that maybe causing the disk degeneration.

Disc tissue and chondrocytes cultured using a variety of techniques synthesize proteoglycans and collagen type II. These culture systems can be used to manipulate the biology using growth factors, gene therapy methods and environmental cues to increase proteoglycans or collagen II production. Human OP-1 has been shown to increase proteoglycan synthesis while collagen type II can be increased when cultures are exposed to recombinant human BMP. Unfortunately, growth factors have a short half life and must therefore be administered in multiple doses to prolong their effect.

The potential solution may be the use of viral vector or gene therapy. When a viral vector with an exogenous gene is introduced into cell cultures, the gene is incorporated into the target cell which can express the gene producing growth factors long term. Adenoviral vector systems using a therapeutic gene containing TGF beta 1 promotes both proteoglycan and collagen synthesis. This response is dose dependent. Similarly, anulus fibrosis cell cultures show increased collagen synthesis when exposed to viral vectors carrying BMPs and Sox-9 genes. Combined use of multiple growth factors genes such as TGF beta 1, BMP 2, and IGF has an additive effect on proteoglycan synthesis. The Sox-9 gene is essential for chondrogenesis. It has been shown to promote type II collagen synthesis in disc cell cultures. In animal studies adeno Sox-9 inoculation of the disc maintains normal disc anatomy while controls show disc degeneration and osteophyte formation.

To date, studies show that growth factors may slow the degenerative process but not reverse it. Disc chondrocytes are sparse in numbers and difficult to isolate and culture. Mesenchymal stem cells grown in an hypoxic environment will produce collagen and Sox-9 markers similar to nucleus pulposus cells. Cells harvested from the disc and grown in culture will survive and synthesis matrix when retransplanted into the disc environment. If suitable cells can be cultured and genetically manipulated to up regulate growth factor production, then introduction of these cells into a degenerating disc at an appropriate stage might favorably moderate the degenerative process hopefully obviating the need for surgery.

INTRODUCTION: Posterolateral intertransverse lumbar fusion is a commonly performed procedure for stabilisation of the degenerated lumbar spine. A typical clinical scenario for which such fusions are used is the stabilisation of a degenerative spondylolisthesis after decompression. In a recent large series reported in the literature, this type of fusion was noted to have a pseudarthrosis rate of up to 45% (Fischgrund, Spine 1997).

METHODS: A pilot study was designed to evaluate the safety and efficacy of osteoinductive protein-1 (OP-1, also known as recombinant human BMP-7) in lumbar posterolateral fusion. Thirty-six patients with the diagnosis of symptomatic spinal stenosis and single level degenerative spondylolisthesis in the lower lumbar spine (L3–S1) were enrolled. The patients were randomised to either the OP-1 group or the control group. The OP-1 group received 3.5 mg of OP-1 per side in a putty carrier. The control group received iliac crest autograft alone. Outcomes were measured clinically using the Oswestry score and radiographically using dynamic radiographs evaluated independently by two blinded radiologists using digital calipers. Patients were deemed a clinical success if they showed a > 20% improvement in Oswestry score and were deemed a radiographic success if they showed bridging bone and spinal stability on flexion/ extension films.

RESULTS: At twelve months, 18/21 (85.7%) patients in the OP-1 group and 8/11 (72.7%) patients in the autograft group were considered clinical successes, while 13/18 (72.2%) of patients in the OP-1 group and 6/10 (60%) patients in the autograft group were considered radiographic successes. No adverse events related to the use of OP-1 were noted.

DISCUSSION: Despite the non-statistical number of patients enrolled in this pilot study, these preliminary results suggest that OP-1 appears to be a safe and effective replacement for iliac crest autograft in human pos-terolateral lumbar fusion. The OP-1 group had a higher radiographic fusion rate than the autograft group. This correlated well with the greater clinical success experienced by the OP-1 group, as measured by improvement in the Oswestry score. None of the previously reported device related complications related to the use of BMPs in animal studies, such as exuberant bone growth with subsequent neural impingement, ectopic ossification, or spinal stenosis, was seen in the treatment group.

CONCLUSION: OP-1 appears to be a safe and effective replacement for iliac crest autograft in human posterolateral lumbar fusion. The dose, 3.5 mg per side, and the carrier, a biodegradable putty, appear to provide a safe and effective means of delivering the bone morphogenetic protein OP-1 to the human lumbar spine.