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Gregory A. Helm and Zulma Gazit

Stem cells are currently being studied for use in numerous clinical applications, ranging from neurodegenerative diseases to cardiac insufficiency. The use of mesenchymal stem cells (MSCs) in spine surgery is also compelling, especially with the increasing age of the general population. In this review the authors discuss the use of MSCs for intervertebral disc repair and regeneration and for use in spinal arthrodesis procedures. Clearly, the routine use of cellular therapies by spine surgeons to improve outcome after a variety of surgical procedures is rapidly approaching.

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Jason P. Sheehan, Gregory A. Helm, Jonas M. Sheehan, and John A. Jane Sr.

Lumbar spinal stenosis can be effectively treated by performing an extensive ipsilateral spinal decompression, including a partial pediculotomy, and contralateral posterior bone fusion. Infrequently, complications can arise following radical decompression to alleviate symptoms of stenosis, and one such complication is a pedicle fracture. Three reports of pedicle fractures following extensive spinal decompression and contralateral posterior fusion are detailed. This complication is emphasized, and interventions are discussed.

Three patients presented with symptoms attributable to lumbar stenosis; they were initially treated with an ipsilateral decompression, achieved in part, through a partial pediculotomy followed by contralateral autologous bone fusion. Initially, all three patients improved postoperatively; however, they later developed neurological symptoms ipsilateral to the side of spinal decompression. Computerized tomography scanning demonstrated pedicle fractures on the decompressed side. This complication has not yet been reported in association with decompression and fusion for lumbar stenosis.

Two of the patients developed leg pain necessitating reoperation whereas the third experienced only mild transient symptoms. The fractured pedicle was removed in one patient; laminar and spinous process fusion was performed again. Another patient underwent a total laminectomy, removal of the fractured pedicle, and bilateral transverse process fusion. Reoperation yielded satisfactory outcomes. The third patient's symptoms resolved without intervention.

Pedicle fractures are a potential complication of extensive lumbar decompression and contralateral posterior fusion. Loading forces from the facets or transverse processes are possibly the cause of such fractures. Removal of the fractured pedicle, additional decompression, and enhanced bone fusion are recommended when the symptoms warrant surgical intervention.

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Gregory A. Helm, Hayan Dayoub, and John A. Jane Jr.

In the prototypical method for inducing spinal fusion, autologous bone graft is harvested from the iliac crest or local bone removed during the spinal decompression. Although autologous bone remains the “gold standard” for stimulating bone repair and regeneration, modern molecular biology and bioengineering techniques have produced unique materials that have potent osteogenic activities. Recombinant human osteogenic growth factors, such as bone morphogenetic proteins, transforming growth factor–β, and platelet-derived growth factor are now produced in highly concentrated and pure forms and have been shown to be extremely potent bone-inducing agents when delivered in vivo in rats, dogs, primates, and humans. The delivery of pluripotent mesenchymal stem cells (MSCs) to regions requiring bone formation is also compelling, and it has been shown to be successful in inducing osteogenesis in numerous pre-clinical studies in rats and dogs. Finally, the identification of biological and nonbiological scaffolding materials is a crucial component of future bone graft substitutes, not only as a delivery vehicle for bone growth factors and MSCs but also as an osteoconductive matrix to stimulate bone deposition directly. In this paper, the currently available bone graft substitutes will be reviewed and the authors will discuss the novel therapeutic approaches that are currently being developed for use in the clinical setting.

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Gregory A. Helm, Hayan Dayoub, and John A. Jane Jr.

Numerous mesenchymal growth factors with osteogenic properties have now been identified. Although many of these proteins can induce bone formation when delivered on a carrier matrix, these approaches have not been fully developed in the laboratory or clinic. The expression of osteogenic proteins via direct or ex vivo gene therapy techniques is also compelling because high-level, long-term gene expression can now be achieved using novel viral and nonviral vectors. In this brief review the authors will highlight recent advances in genetic therapies for the induction of osteogenesis, as well as their potential use for the promotion of spinal arthrodesis.

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Thomas C. Chen and Gregory A. Helm

Gene therapy is an exciting new discipline in which neurosurgery and neurosurgeons can have a direct impact on both patient care and emerging scientific developments. Unlike other organs, the brain is unique in that it has a blood–brain barrier, often preventing efficient systemic gene delivery to the area of interest. Therefore, not only is gene delivery required, but it will often need to be accomplished in a local and specific manner. Although brain neoplasms have been the most commonly studied application of genetic therapeutics in neurological surgery, there are many other potential applications of this technology to neurosurgical disorders, including spinal instability, neurodegenerative disease, neurogenetic diseases, central nervous system (CNS) injury, aneurysms, trauma, stroke, and epilepsy. As the field of gene therapy for the CNS develops from the preclinical setting to clinical trials to mainstream therapy, the need for safe and specific gene delivery will be increasingly apparent. Neurosurgeons are in an enviable position as there is nobody more qualified to address the issue of how a gene can be delivered to the central nervous system. Not only do we have the training to operate on the nervous system and its coverings, but we have the ability to recognize and take care of complications that may arise from these procedures. However, the neurosurgeon's role in gene therapy for the brain and spine should not be confined to gene delivery only. Instead, we also need to understand and have a role in deciding what genes could have therapeutic utility in our patients. Herein lies our challenge in gene therapy: how can we as neurosurgeons interface with our basic science colleagues to address rapidly all of the problems that are blocking the advancement of nucleic acid therapeutics into the clinical setting.

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Gregory A. Helm, Jin Zhong Li, Tord D. Alden, Sarah A. Hudson, Elisa J. Beres, Mary Cunningham, Mark M. Mikkelsen, Debra D. Pittman, Kelvin M. Kerns, and David F. Kallmes

Object

Bone morphogenetic proteins (BMPs) are involved in the growth and development of many tissues, but it is their role in skeletal development and their unique ability to induce ectopic and orthotopic osteogenesis that has attracted the greatest interest. Expression of the BMP-13 gene has been shown to be predominantly localized to hypertrophic chondrocytes in regions of endochondral bone formation during development, as well as in mature articular cartilage in the adult. In addition, the application of BMP-13 on a collagen carrier induces neotendon/ligament formation when delivered subcutaneously or intramuscularly in rodents. The aim of the present study was to determine the histological and ultrastructural changes that occur after the intramuscular injection of a first-generation BMP-13 adenoviral vector.

Methods

Athymic nude rats were injected with 3.75 × 1010 plaque-forming unit adenovirus (Ad)-BMP-13 or Ad-β-galactosidase in the thigh musculature, and the regions examined using light and electron microscopy at various time points between 2 and 100 days postinjection. As early as 2 days after injection of Ad-BMP-13, progenitor cells were observed infiltrating between the transduced muscle fibers. These cells subsequently proliferated, differentiated, and secreted large amounts of collagenous extracellular matrix. By 100 days postinjection, the induced tissue had the histological and ultrastructural appearance of neotendon/ligament, which was clearly demarcated from the surrounding muscle. Small foci of bone and fibrocartilage were also seen within the induced tissue. A short-term bromodeoxyuri-dine study also demonstrated rapid mesenchymal cell proliferation at the Ad-BMP-13 injection site as early as 48 hours postinjection.

Conclusions

The results of this study suggest that in the future the use of the BMP-13 gene may have therapeutic utility for the healing of tendon and ligament tears and avulsion injuries.

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Tord D. Alden, Gerald R. Hankins, Elisa J. Beres, David F. Kallmes, and Gregory A. Helm

Gene therapy has many potential applications in neurosurgery. One application involves bone morphogenetic protein-2 (BMP-2), a low-molecular-weight glycoprotein that induces bone formation in vivo. Numerous studies have demonstrated that the BMP-2 protein can enhance spinal fusion. This study was undertaken to determine whether direct injection of an adenoviral construct containing the BMP-2 gene can be used for spinal fusion. Twelve athymic nude rats were used in this study. Recombinant, replication-defective type-5 adenovirus with a universal promoter and BMP-2 gene (Ad-BMP-2) was used. A second adenovirus constructed with a universal promoter and ß-galactosidase (ß-gal) gene (Ad-ß-gal) was used as a control. Seven and one-half microliters of virus was injected percutaneously and paraspinally at the lumbosacral junction in three groups (four animals each): 1) Ad-BMP-2 bilaterally, 2) Ad-BMP-2 on the right, Ad-ß-gal on the left, and 3) Ad-ß-gal bilaterally. Computerized tomography (CT) scans of the lumbosacral spine were obtained at 3, 5, and 12 weeks. At 12 weeks, the animals were killed for histological inspection. Ectopic bone formation was seen both on three-dimensional CT reconstruction and histologically in all rats at sites treated with Ad-BMP-2. Histological analysis revealed bone at different stages of maturity adjacent to the spinous processes, laminae, and transverse processes. This study clearly demonstrated that it is possible to produce in vivo endochondral bone formation by using direct adenoviral construct injection into the paraspinal musculature, which suggests that gene therapy may be useful for spinal fusion in the future.

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John E. Wanebo, Hunter G. Louis, Adam S. Arthur, Jie Zhou, Neal F. Kassell, Kevin S. Lee, and Gregory A. Helm

Cerebral vasospasm is a major complication of subarachnoid hemorrhage (SAH) after the rupture of an intracranial aneurysm. Although the cause of cerebral vasospasm has not been fully established, several lines of evidence suggest that the vasoconstrictor peptide endothelin (ET) may play a crucial role. In the present study the potential of TBC 11251 (TBC), a newly developed ETA receptor antagonist, to prevent and/or reverse cerebral vasospasm was examined in a well-established rabbit model of SAH.

Sixty-five New Zealand White rabbits were assigned to one of six groups. Experimental SAH was induced in rabbits comprising five of the groups by injecting autologous arterial blood into the cisterna magna. The treatment groups were as follows: 1) control (no SAH); 2) SAH only; 3) SAH + placebo at 24 and 36 hours (24/36); 4) SAH + TBC (24/36); 5) SAH + placebo twice daily (BID); and 6) SAH + TBC BID. All drug-treated animals received an intravenous dosage of 5 mg/kg TBC. After 48 hours, the animals were killed by intracardiac perfusion with fixative. The brainstems were removed and the basilar arteries (BAs) were prepared for histological examination. The cross-sectional area of each BA was measured using computer-assisted videomicroscopy by an investigator blind to the group from which it came. A one-way analysis of variance and paired group mean comparisons with the post-hoc Fisher least significant difference test were used for analysis of BA diameters and physiological parameters.

The model provided reliable vasospasm, with the mean BA cross-sectional area constricting from 0.388 mm2 in the control group to 0.106 mm2 (27.4% of control) in the SAH only group. Treatment with TBC (24/36) after SAH (reversal protocol) produced a mean BA area of 0.175 mm2 (44.2% of control) which, although larger than the placebo group value of 0.135 mm2 (39.9% of control), was not statistically significant. However, treatment with TBC BID (prevention protocol) produced a mean BA area of 0.303 mm2 (78.1% of control) compared with the placebo BID value of 0.134 mm2 (34.6% of control); this effect was statistically significant (p < 0.01). There were no side effects noted and no differences in the mean arterial pressures between drug and placebo groups.

These findings demonstrate that systemic administration of the ETA receptor antagonist TBC significantly attenuates cerebral vasospasm after SAH when given as a preventative therapy, and they provide additional support for the role of ET in the establishment of vasospasm.

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John A. Jane Jr., Charles G. diPierro, Gregory A. Helm, Christopher I. Shaffrey, and John A. Jane Sr.

Stenosis of the central and lateral lumbar vertebral canal can be congenital or acquired; the latter is most often caused by a degenerative process. The associated neurogenic claudication and/or radiculopathic symptom complexes are thought to result from compression of the cauda equina and lumbosacral nerve roots by hypertrophy of or encroachment by any combination of the following: canal walls, ligamenta flava, intervertebral discs, posterior longitudinal ligament, or epidural fat.

The authors' technique for the treatment of lumbar stenosis involves extensive unilateral decompression with undercutting of the spinous process and obviates the need for instrumentation by using a contralateral autologous bone fusion. The results in a series of 29 patients in whom the procedure was performed suggest that this decompression method safely and successfully treats not only the radicular symptoms caused by lateral stenosis but also the neurogenic claudication symptoms associated with central stenosis. In addition, the procedure can preserve spinal stability without instrumentation by using contralateral autologous bone fusion along the laminae and spinous processes.