Paul T. Rubery

Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy

Structural allograft healing is limited because of a lack of vascularization and remodeling. To study this we developed a mouse model that recapitulates the clinical aspects of live autograft and processed allograft healing. Gene expression analyses showed that there is a substantial decrease in the genes encoding RANKL and VEGF during allograft healing. Loss-of-function studies showed that both factors are required for autograft healing. To determine whether addition of these signals could stimulate allograft vascularization and remodeling, we developed a new approach in which rAAV can be freeze-dried onto the cortical surface without losing infectivity. We show that combination rAAV-RANKL- and rAAV-VEGF-coated allografts show marked remodeling and vascularization, which leads to a new bone collar around the graft. In conclusion, we find that RANKL and VEGF are necessary and sufficient for efficient autograft remodeling and can be transferred using rAAV to revitalize structural allografts.

Periosteal progenitor cell fate in segmental cortical bone graft transplantations: implications for functional tissue engineering.

A murine segmental femoral bone graft model was used to show the essential role of donor periosteal progenitor cells in bone graft healing. Transplantation of live bone graft harvested from Rosa 26A mice showed that ∼70% of osteogenesis on the graft was attributed to the expansion and differentiation of donor periosteal progenitor cells. Furthermore, engraftment of BMP‐2‐producing bone marrow stromal cells on nonvital allografts showed marked increases in cortical graft incorporation and neovascularization, suggesting that gene‐enhanced, tissue engineered functional periosteum may improve allograft incorporation and repair.

Teriparatide May Accelerate Healing in Delayed Unions of Type Iii Odontoid Fractures: A Report of 3 Cases

Study Design Case Report. Objective To report on the treatment of 3 cases of painful delayed unions of type III odontoid fractures with teriparatide. Summary of Background Data Fractures of the C2 vertebra, also known as odontoid fractures, are an important subset of cervical spine fractures. Type III odontoid fractures pass through predominately cancellous bone of C2. Generally accepted treatment is external immobilization with either a rigid collar or a halo vest for 8 to 12 weeks. We report 3 patients who, despite external immobilization, developed painful delayed unions of type III odontoid fractures. Teriparatide is a novel anabolic drug therapy for osteoporosis. It has been shown to stimulate osteoblasts, enhance bone connectivity, increase endosteal cortical thickness, and improve bone mineral content. The drug is given through subcutaneous injection of 20 μg/d for between 6 weeks and 2 years. We treated these 3 patients with teriparatide. Each was informed that details of their case would be submitted for publication. Methods Retrospective case analysis. Results All 3 patients experienced both rapid clinical improvement and computed tomography evidence of fracture union. Conclusion These 3 cases represent relatively uncommon clinical scenarios in which type III odontoid fractures in osteoporotic women failed to unite with external immobilization over several months. The patients presented for follow-up with substantial, activity-limiting neck pain. All 3 were begun on teriparatide doses therapeutic for osteoporosis, and all 3 experienced both remarkable resolution of chronic neck pain and computed tomography-confirmed union of the fractures.

Athletic activity after spine surgery in children and adolescents: results of a survey.

Study Design. Questionnaire-based survey. Objectives. To poll the members of the Scoliosis Research Society regarding their opinions and experience with athletic activity after spine surgery performed on children and adolescents. Summary of Background Data. Athletic activity is increasingly important in society. Patients are very concerned about returning to sports and exercise after spinal surgery. There are no generally accepted guidelines for surgeons regarding either appropriate sports or the appropriate time to resume sports after spinal surgery. Methods. A survey was designed by the authors and reviewed by a statistical consultant. The form was mailed to the 721 individuals on the Scoliosis Research Society mailing list. Returned surveys were hand scored and entered into an Excel spreadsheet. Results. Of the 316 forms returned, 278 indicated that the respondent performed spinal fusion on children and adolescents. Two hundred sixty-one completed forms, representing approximately 45% of the society’s estimated active clinicians, were reviewed. Formal physical therapy was unlikely to be recommended by members of the society regardless of procedure, although postoperative home exercise was used by many after spondylolisthesis fusion. The majority of patients were returned to gym class between 6 months and 1 year (range, immediate to never) after surgery. Most respondents returned patients to noncontact sports between 6 months and 1 year postoperatively. Contact sports were generally withheld until 1 year after surgery. Close to 20% of respondents required, and 35% suggested, that patients never return to collision sports. Twenty percent of respondents for scoliosis and 5% for spondylolisthesis reported having notable adverse outcomes attributed to athletic activity. Conclusion. These survey results show the varying approaches taken by members of the Scoliosis Research Society to postoperative athletic activity, and they provide a starting point for investigations regarding alternative approaches.

Conditional activation of β‐catenin signaling in mice leads to severe defects in intervertebral disc tissue

OBJECTIVE The incidence of low back pain is extremely high and is often linked to intervertebral disc (IVD) degeneration. The mechanism of this disease is currently unknown. This study was undertaken to investigate the role of β-catenin signaling in IVD tissue function. METHODS β-catenin protein levels were measured by immunohistochemical analysis of disc samples obtained from patients with disc degeneration and from normal subjects. To generate β-catenin conditional activation (cAct) mice, Col2a1-CreER(T2) -transgenic mice were bred with β-catenin(fx(Ex3)/fx(Ex3)) mice. Changes in disc tissue morphology and function were examined by micro-computed tomography, histologic analysis, and real-time polymerase chain reaction assays. RESULTS β-catenin protein was up-regulated in disc tissue samples from patients with disc degeneration. To assess the effects of increased β-catenin levels on disc tissue, we generated β-catenin cAct mice. Overexpression of β-catenin in disc cells led to extensive osteophyte formation in 3- and 6-month-old β-catenin cAct mice, which were associated with significant changes in the cells and extracellular matrix of disc tissue and growth plate. Gene expression analysis demonstrated that activation of β-catenin enhanced runt-related transcription factor 2-dependent Mmp13 and Adamts5 expression. Moreover, genetic ablation of Mmp13 or Adamts5 on the β-catenin cAct background, or treatment of β-catenin cAct mice with a specific matrix metalloproteinase 13 inhibitor, ameliorated the mutant phenotype. CONCLUSION Our findings indicate that the β-catenin signaling pathway plays a critical role in disc tissue function.

Mycotic aortic aneurysm in patients who have lumbar vertebral osteomyelitis. A report of two cases.

The diagnosis and treatment of vertebral osteomyelitis have been documented in several reports4 9’3’5. Despite the proximity of the vertebral bodies and the discs to the visceral, vascular, and neurological structures of the retroperitoneum, we know of few reports that document the extraspinal complications of vertebra! osteomyelitis. We report the cases of two patients with vertebral osteomyelitis who had a mycotic aneurysm of the aorta. One of the patients had a spontaneous rupture of the aneurysm with catastrophic results. The presentation, management, and follow-up of these patients, as well as the pitfalls of the treatment of osteomyelitis of the vertebral body, are discussed in order to emphasize the risk of potentially catastrophic vascular complications.

Comparison of 4 airway devices on cervical spine alignment in a cadaver model with global ligamentous instability at C5-C6.

Study Design. Human cadaveric study using various intubation devices in a cervical spine instability model. Objective. We sought to evaluate various intubation techniques and determine which device results in the least cervical motion in the setting of a global ligamentous instability model. Summary of Background Data. Many patients presenting with a cervical spine injury have other injuries that may require rapid airway management with endotracheal intubation. Secondary neurologic injuries may occur in these patients because of further displacement at the level of injury, vascular insult, or systemic decrease in oxygen delivery. The most appropriate technique for achieving endotracheal intubation in the patient with a cervical spine injury remains controversial. Methods. A global ligamentous instability at the C5–C6 vertebral level was created in lightly embalmed cadavers. An electromagnetic motion analysis device (Liberty; Polhemus, Colchester, VT) was used to assess the amount of angular and linear translation in 3 planes during intubation trials with each of 4 devices (Airtraq laryngoscope, lighted stylet, intubating LMA, and Macintosh laryngoscope). The angular motions measured were flexion-extension, axial rotation, and lateral bending. Linear translation was measured in the medial-lateral (ML), axial, and anteroposterior planes. Intubation was performed by either an emergency medical technician or by a board-certified attending anesthesiologist. Both time to intubate as well as failure to intubate (after 3 attempts) were recorded. Results. There was no significant difference shown with regards to time to successfully intubate using the various devices. It was shown that the highest failure-to-intubate rate occurred with use of the intubating LMA (ILMA) (23%) versus 0% for the others. In flexion/extension, we were able to demonstrate that the Lightwand (P = 0.005) and Airtraq (P = 0.019) resulted in significantly less angular motion than the Macintosh blade. In anterior/posterior translation, the Lightwand (P = 0.005), Airtraq (P = 0.024), and ILMA (P = 0.021) all caused significantly less linear motion than the Macintosh blade. In axial rotation, the Lightwand (P = 0.017) and Airtraq (P = 0.022) resulted in significantly less angular motion than the Macintosh blade. In axial translation (P = 0.037) and lateral bending (P = 0.003), the Lightwand caused significantly less motion than the Macintosh blade. Conclusion. In a cadaver model of C5–C6 instability, the greatest amount of motion was caused by the most commonly used intubation device, the Macintosh blade. Intubation with the Lightwand resulted in significantly less motion in all tested parameters (other than ML translation) as compared with the Macintosh blade. It should also be noted that the Airtraq caused less motion than the Macintoshblade in 3 of the 6 tested planes. There were no significant differences in failure rate or the amount of time it took to successfully intubate in comparing these techniques. We therefore recommend the use of the Lightwand, followed by the Airtraq, in the setting of a presumed unstable cervical spine injury over the Macintosh laryngoscope.

Scoliosis in familial dysautonomia. Operative treatment.

The results of operative treatment of scoliosis were reviewed for twenty-two patients (ten boys and twelve girls) who had familial dysautonomia, an autosomal recessive disorder affecting primarily Ashkenazi Jews. The indication for operative intervention was progressive kyphoscoliosis to 45 degrees or more in a skeletally immature patient for whom bracing had failed. The mean age at the time of the operation was fifteen years and five months (range, eight years and two months to nineteen years). Seventeen patients had a thoracic curve with a mean preoperative Cobb angle of 69 degrees (range, 47 to 112 degrees), and five patients had a double major curve with a mean preoperative Cobb angle of 71 degrees (range, 42 to 87 degrees) for the cephalad curves and 60 degrees (range, 45 to 72 degrees) for the caudad curves. Twenty patients had a rigid kyphosis; in fourteen, the apex was at the seventh thoracic vertebra or more cephalad. Two patients had a lordoscoliosis. The mean preoperative kyphosis was 64 degrees (range, 12 to 110 degrees) in the thirteen patients who had a thoracic curve and for whom information regarding kyphosis was available, and it was 70 degrees (range, 54 to 84 degrees) in the five patients who had a double major curve. Postoperior spinal arthrodesis and instrumentation was performed in all patients. Two patients had an anterior arthrodesis as well because of the severity and rigidity of the curve. Allograft bone was used in eighteen patients. Postoperatively, all patients were managed with a body cast or with a custom-molded thoracolumbar brace.(ABSTRACT TRUNCATED AT 250 WORDS)

Unstable Subaxial Cervical Spine Injury With Normal Computed Tomography and Magnetic Resonance Initial Imaging Studies: A Report of Four Cases and Review of the Literature

Study Design. Case series. Objective. To describe 4 cases of unstable subaxial cervical spine injury not demonstrated with initial radiograph, computed tomography (CT), and magnetic resonance (MR) imaging. Summary of Background Data. When evaluating the cervical spine for ligamentous or osseous injuries in the blunt trauma patient population, negative predictive value measurements of 100% for CT and MR imaging have been published. Unstable subaxial cervical spine injury has rarely been reported in the spine literature in conjunction with initial radiograph, CT, and MR imaging demonstrating no osseous or ligamentous injury. Historically, reports of subacute cervical spine instability following trauma exist and were presented before the availability of MR and multidetector CT imaging. Methods and Results. We report 4 examples of unstable subaxial cervical spine injury each with initial imaging interpreted as negative. All 4 cases presented at a level-one tertiary care facility. Follow-up radiographs demonstrated unstable cervical spine injuries requiring surgical stabilization. Conclusion. Notwithstanding high sensitivities, specificities, and negative predictive values for cervical spine imaging and “clearance” mechanisms, 4 cases that illustrate the potential for undetected unstable cervical spine injuries are presented. Tremendous advancements in medical imaging have been made. However, radiograph, CT, and MR imaging may still fail to accurately translate the anatomic and dynamic complexity of the cervical spine into digital images that accurately guide clinical practice. A full understanding of and keen appreciation for the fact that no imaging technique, classification method, or clearance protocol can produce 100% sensitivity at all times is essential. These case reports cumulatively demonstrate a 0.04% to 0.2% incidence of undetected cervical injury requiring surgical stabilization. Removing cervical collar immobilization as quickly as possible based on negative interpretation of imaging data may prove harmful in a measurable percentage of patients and must be undertaken with caution only after clinical correlation and strict follow-up is established.

Correlation of PROMIS Physical Function and Pain CAT Instruments With Oswestry Disability Index and Neck Disability Index in Spine Patients.

Study Design. A prospective and retrospective cross-sectional cohort analysis. Objective. The aim of this study was to show that Patient-Reported Outcomes Measurement Information System (PROMIS) computer adaptive testing (CAT) assessments for physical function and pain interference can be efficiently collected in a standard office visit and to evaluate these scores with scores from previously validated Oswestry Disability Index (ODI) and Neck Disability Index (NDI) providing evidence of convergent validity for use in patients with spine pathology. Summary of Background Data. Spinal surgery outcomes are highly variable, and substantial debate continues regarding the role and value of spine surgery. The routine collection of patient-based outcomes instruments in spine surgery patients may inform this debate. Traditionally, the inefficiency associated with collecting standard validated instruments has been a barrier to routine use in outpatient clinics. We utilized several CAT instruments available through PROMIS and correlated these with the results obtained using “gold standard” legacy outcomes measurement instruments. Methods. All measurements were collected at a routine clinical visit. The ODI and the NDI assessments were used as “gold standard” comparisons for patient-reported outcomes. Results. PROMIS CAT instruments required 4.5 ± 1.8 questions and took 35 ± 16 seconds to complete, compared with ODI/NDI requiring 10 questions and taking 188 ± 85 seconds when administered electronically. Linear regression analysis of retrospective scores involving a primary back complaint revealed moderate to strong correlations between ODI and PROMIS physical function with r values ranging from 0.5846 to 0.8907 depending on the specific assessment and patient subsets examined. Conclusion. Routine collection of physical function outcome measures in clinical practice offers the ability to inform and improve patient care. We have shown that several PROMIS CAT instruments can be efficiently administered during routine clinical visits. The moderate to strong correlations found validate the utility of computer adaptive testing when compared with the gold standard “static” legacy assessments. Level of Evidence: 4