Claire F. Jones

A Novel Porcine Model of Traumatic Thoracic Spinal Cord Injury

Spinal cord injury (SCI) researchers have predominately utilized rodents and mice for in vivo SCI modeling and experimentation. From these small animal models have come many insights into the biology of SCI, and a growing number of novel treatments that promote behavioral recovery. It has, however, been difficult to demonstrate the efficacy of such treatments in human clinical trials. A large animal SCI model that is an intermediary between rodent and human SCI may be a valuable translational research resource for pre-clinically evaluating novel therapies, prior to embarking upon lengthy and expensive clinical trials. Here, we describe the development of such a large animal model. A thoracic spinal cord injury at T10/11 was induced in Yucatan miniature pigs (20-25 kg) using a weight drop device. Varying degrees of injury severity were induced by altering the height of the weight drop (5, 10, 20, 30, 40, and 50 cm). Behavioral recovery over 12 weeks was measured using a newly developed Porcine Thoracic Injury Behavior Scale (PTIBS). This scale distinguished locomotor recovery among animals of different injury severities, with strong intra-observer and inter-observer reliability. Histological analysis of the spinal cords 12 weeks post-injury revealed that animals with the more biomechanically severe injuries had less spared white matter and gray matter and less neurofilament immunoreactivity. Additionally, the PTIBS scores correlated strongly with the extent of tissue sparing through the epicenter of injury. This large animal model of SCI may represent a useful intermediary in the testing of novel pharmacological treatments and cell transplantation strategies.

The Effect of Cerebrospinal Fluid on the Biomechanics of Spinal Cord: An ex Vivo Bovine Model Using Bovine and Physical Surrogate Spinal Cord

Study Design. A biomechanical study using ex vivo bovine spinal cord and dura, and a synthetic surrogate spinal cord with bovine dura. Objective. To investigate the effect of cerebrospinal fluid (CSF) on spinal cord deformation characteristics and to evaluate the biofidelity of a new surrogate spinal cord using an ex vivo bovine model of the burst fracture process. Summary of Background Data. Spinal cord injury is associated with significant personal, economic and social costs. The role of CSF during the injury event and its effect on the spinal cord deformation and neurologic injury is not well understood. Such knowledge could inform preventative strategies and clinical interventions and aid the development and validation of experimental and computational models. Methods. The transverse impact of a propelled bone fragment analogue with bovine and surrogate cord models was recorded with high speed video and the images analyzed to determine deformation trajectories. Each cord specimen was tested in 3 states: with dura and CSF, with dura only, and without dura. The effect of these states on deformation magnitude, duration, and energy loss parameters was assessed. Results. The estimated spinal cord deformation was significantly reduced, although not eliminated, in the presence of CSF when compared to the bare state. The duration of deformation was generally increased in the presence of CSF, though this difference was not statistically significant. This may indicate a reduction in the cord-fragment interaction force for a given impulse. The dura was found to have no significant effect on deformation parameters for the bovine spinal cord. The deformation of the surrogate cord gave similar trends for the different states in comparison to the bovine cord, but was significantly less than the bovine spinal cord for all conditions. Conclusion. The results indicate that the protective mechanism of CSF may not eliminate cord deformationunder the high energy transverse impact characteristic of a burst fracture. However, CSF may contribute to a lessening of cord deformation and applied force.

The pressure distribution of cerebrospinal fluid responds to residual compression and decompression in an animal model of acute spinal cord injury.

Study Design. In vivo large animal (pig) model study of cerebrospinal fluid (CSF) pressures after acute experimental spinal cord injury (SCI). Objective. To determine how the CSF pressure (CSFP) and CSF pulse pressure amplitude (CSFPPA) cranial and caudal to the injury site change after an acute SCI with subsequent thecal occlusion and decompression. Summary of Background Data. Lowering intrathecal pressure via CSF drainage is currently instituted to prevent ischemia-induced SCI during thoracoabdominal aortic aneurysm surgery and was recently investigated as a potential intervention for acute traumatic SCI. However, in SCI patients, persistent extradural compression commonly occludes the subarachnoid space. This may generate a CSFP differential across the injury site, which cannot be appreciated with lumbar catheter pressure measurements. Methods. Anesthetized pigs were subjected to an acute contusive SCI at T11 and 8 hours of sustained compression (n = 12), or sham surgery (n = 2). CSFP was measured cranial and caudal to the injury site, using miniature pressure transducers, during compression and for 6 hours after decompression. Results. The cranial-caudal CSFP differential increased (mean, 0.39 mm Hg/h), predominantly due to increased cranial pressure. On decompression, cranial CSFP decreased (mean, –1.16 mm Hg) and caudal CSFP increased (mean, 0.65 mm Hg). The CSFP differential did not change significantly after decompression. Cranial CSFPPA was greater than caudal CSFPPA, but this differential did not change during compression. On decompression, the caudal CSFPPA increased in some but not all animals. Conclusion. Although extradural compression exists at the site of injury, lumbar CSFP may not accurately indicate CSFP cranial to the injury. Decompression may provide immediate, though perhaps partial, resolution of the pressure differential. CSFPPA was not a consistent indicator of decompression in this animal model. These findings may have implications for the design of future clinical protocols in which CSFP is monitored after acute SCI.

Gross morphological changes of the spinal cord immediately after surgical decompression in a large animal model of traumatic spinal cord injury.

Study Design. Quantitative in vivo ultrasound imaging study of spinal cord and dura morphology after acute experimental spinal cord injury (SCI) and decompression in a pig model. Objective. To study the morphological changes of the spinal cord and dura immediately after surgical decompression for acute SCI. Summary of Background Data. Surgical decompression for traumatic SCI is currently a topic of debate. After decompression, relief of bony impingement on the thecal sac and spinal cord can be confirmed intraoperatively. However, postoperative imaging often reveals that the cord has swollen to fill the subarachnoid space. Little is known about the extent and timing of this morphological response. Methods. Yucatan miniature pigs received sham surgery (N = 1) or a moderate (N = 6, 20 g, 2.3 m/s) or high (N = 6, 20 g, 4.7 m/s) severity weight-drop SCI followed by 8 hours of sustained compression (100 g) and 6 hours of postdecompression monitoring. Sagittal-plane ultrasound images were used to quantify spinal cord, dura, and subarachnoid space dimensions preinjury and once per hour after decompression. Results. Animals with a moderate SCI exhibited a residual cord deformation of up to 0.64 mm within 10 minutes of decompression, which tended to resolve during 6 hours because of tissue relaxation and swelling. For animals with high-severity SCIs, cord swelling was immediate and resulted in occlusion of the subarachnoid space within 10 minutes to 5 hours, whereas this occurred for only half of the moderate injury group. Conclusion. Decompression of an acute SCI may result in residual cord deformation followed by gradual swelling or immediate swelling leading to subarachnoid occlusion. The response is dependent on initial injury severity. These observations may partly explain the lack of benefit of decompression in some patients and suggest a need to reduce cord swelling to optimize the clinical outcome after acute SCI.

Surveillance strategies according to the rate of growth of small abdominal aortic aneurysms

The management of small abdominal aortic aneurysms (AAA) is by ultrasound surveillance. The study aimed to calculate their growth rate, identify risk factors and determine appropriate screening intervals. The local screening programme and hospital records were used to identify patients with a small (< 5.5 cm) AAA. The dates and maximum diameter of serial scans of patients with two or more scans were obtained. Patients were subdivided by 0.5 cm increments above 3.0 cm. The rate of growth was calculated by linear regression for each patient using both the absolute measurements and logarithmically (ln) transformed measurements. The 95th centile of growth rate within each subgroup was used to estimate the minimum time to grow to 5.5 cm. A total of 252 were included. The mean (± SD) AAA size on the initial scan was 3.9 (± 0.7) cm. Statin use and initial size were predictive factors for the growth rate. The median rate of growth increased according to size from 0.075 to 0.432 cm/year for AAA < 3.5 cm and > 5.0 cm, respectively. It also steadily increased for ln measurements from 0.022 (or 2.2%/year) to 0.078 or (7.8%/year). The minimum time (months) to reach 5.5 cm was 61, 17, 11 and 5 for AAA < 3.5 cm, 3.5–3.9 cm, 4.0–4.4 cm and 4.5–4.9 cm, respectively. Based on ln measurements, the times were similar at 60, 17, 10 and 4 months. In conclusion, the rate of growth increased steadily with AAA size. An aneurysm < 3.5 cm does not require a repeat scan for 5 years, while those measuring 3.5–3.9 cm and 4.0–4.4 cm require a repeat scan after 17 and 11 months.

The development of an improved physical surrogate model of the human spinal cord--tension and transverse compression.

To prevent spinal cord injury, optimize treatments for it, and better understand spinal cord pathologies such as spondylotic myelopathy, the interaction between the spinal column and the spinal cord during injury and pathology must be understood. The spinal cord is a complex and very soft tissue that changes properties rapidly after death and is difficult to model. Our objective was to develop a physical surrogate spinal cord with material properties closely corresponding to the in vivo human spinal cord that would be suitable for studying spinal cord injury under a variety of injurious conditions. Appropriate target material properties were identified from published studies and several candidate surrogate materials were screened, under uniaxial tension, in a materials testing machine. QM Skin 30, a silicone elastomer, was identified as the most appropriate material. Spinal cords manufactured from QM Skin 30 were tested under uniaxial tension and transverse compression. Rectangular specimens of QM Skin 30 were also tested under uniform compression. QM Skin 30 produced surrogate cords with a Youngs modulus in tension and compression approximately matching values reported for in vivo animal spinal cords (0.25 and 0.20 MPa, respectively). The tensile and compressive Youngs modulus and the behavior of the surrogate cord simulated the nonlinear behavior of the in vivo spinal cord.

Allogeneic Mesenchymal Precursor Cells Promote Healing in Postero-lateral Annular Lesions and Improve Indices of Lumbar Intervertebral Disc Degeneration in an Ovine Model

Study Design. In-vivo ovine model of intervertebral disc degeneration (IVD) to evaluate treatment with stem cells. Objective. To determine if stem cells delivered to the nucleus pulposus (NP) or the annulus fibrosus (AF) of degenerated lumbar IVDs leads to improved indices of disc health. Summary of Background Data. Previous studies assessing the efficacy of stem cell injections into degenerated IVDs have reported positive findings. However, studies have been limited to small animals, targeting solely the NP, with short term follow-up. Methods. Mesenchymal precursor cells (MSC) were obtained from the iliac crest of 8-week-old sheep. IVD degeneration was induced by postero-lateral annulotomy at three lumbar levels in eight 2-year-old sheep. Six months later, each degenerated IVD was randomized to one of three treatments: Injection of MSC into (i) previously incised AF (AFI), (ii) NP (NPI), or (iii) no injection (negative control, NC). The adjacent IVD received injection of phosphate buffered saline into NP (positive control, PC). Radiographs and magnetic resonance imaging scans were obtained at baseline, 6, 9, and 12 months. Discs were harvested at 12 months for biochemical and histological analyses. Results. IVD degeneration was consistently observed postannulotomy, and characterized by reduced disc height index (DHI), disc height (DH), glycosaminoglycan (GAG) content, and increased grade of disc degeneration. Six months after stem cell injection, DHI and DH had recovered in AFI and NPI groups when compared with NC group (P < 0.01). Mean Pfirrmann grade improved from 3.25 to 2.67 (AFI group) and from 2.96 to 2.43 (NPI group). Mean histopathological grade improved for both AFI (P < 0.002) and NPI (P < 0.02) groups. Both AFI and NPI groups demonstrated spontaneous repair of the postero-lateral annular lesion. Conclusion. In this large animal model, injection of MSCs into the annulus fibrosus or the nucleus pulposus of degenerated IVD resulted in significant improvements in disc health. Level of Evidence: N/A

A novel analytical approach for determining the frictional moments and torques acting on modular femoral components in total hip replacements

A three dimensional analytical approach was developed to determine the frictional moment vector generated by the relative sliding of the head-cup bearing couple of a total hip replacement. The frictional moment projection onto the femoral neck was also determined over the loading cycle. Predicted frictional moments for nine combinations of bearing materials and diameters were in close agreement with existing in vitro data. The analytical method was then applied to simplified gait (lubrication conditions of dry and serum), ISO standard gait and physiological level gait loading cycles. ISO standard gait had a total contact force of about two fold of physiological level gait and there was a corresponding increase in the maximum frictional torque on neck from 0.66×BW%m to 0.88×BW%m. For the ISO standard gait, the maximum frictional torque occurred at the same instance of maximum frictional moment and the maximum contact force. In contrast, for the physiological level gait, the frictional torque did not occur at the same instance as the peak load. This suggests that the neck frictional torque is a function of other parameters, such as angle between neck axis and frictional moment vector, as well as the magnitude of the contact force and frictional moment. The developed methodology was able to predict the maximum magnitude and change of directions of moments and the variation of torque at the head neck interface. The data will be useful for experimental studies assessing the fretting behaviour of the head neck junction, by providing appropriate loading data.

Impaction bone grafting has potential as an adjunct to the surgical stabilisation of osteoporotic tibial plateau fractures: Early results of a case series.

INTRODUCTION Osteoporotic tibial plateau fractures (TPFs) are difficult to treat with either open reduction internal fixation (ORIF) or acute total knee arthroplasty (TKA). They have high complication rates, poor outcomes and often fail in the short- to mid-term. We investigated the use of impaction bone grafting (IBG) as an adjunct to stabilise the fracture in a cohort of osteoporotic TPFs. METHODS Nine consecutive osteoporotic TPFs were surgically stabilised with ORIF augmented with IBG or with IBG alone (one pure depression fracture) using on average allograft from 2 femoral heads/case (range 1-4 heads or 25-100 cm(3)). The median bone mineral density T-score of the patients was -2.9 (-2.5 to -4.5). All patients were mobilised weight-bearing as tolerated immediately after surgery and had regular follow-up to a minimum of 2 years where functional scores were taken and gait was assessed. Fracture reduction was assessed on plain radiographs and computed tomography (CT) scans; maintenance of fracture reduction was monitored using plain radiographs, CT and radiostereometric analysis (RSA). Bone graft remodelling was assessed by comparison of immediate post-operative CT scans with scans at a minimum of 1 year. RESULTS All surgeries were uneventful. All patients progressed to full weight bearing within 6 weeks of surgery and regained a normal gait by 3 months. Seven fractures healed with a cranio-caudal migration of less than 3mm (range 0-2.6mm using RSA and 0-2mm using CT). Two fractures had an isolated posterolateral fragment depression of 13.5mm and 9 mm, respectively, which did not affect the overall joint alignment or clinical outcomes at short-term follow-up. At latest CT follow-up, on average 51% of the graft area (range 36-70%) had remodelled into new host bone. CONCLUSION Impaction bone grafting shows promising results as an adjunct to the surgical stabilisation of osteoporotic TPFs. In this case series the technique provided enough fracture stability for patients to mobilise weight-bearing as tolerated immediately after surgery and achieve full weight-bearing by the sixth postoperative week. There was no failure of fixation and 7 of the 9 cases healed with minimal fracture displacement.

Cytokine response to portal endotoxaemia and neutrophil stimulation in obstructive jaundice.

Introduction An exaggerated proinflammatory response to endotoxaemia can occur in obstructive jaundice. The aims of this study were to determine the hepatic proinflammatory and anti-inflammatory cytokine response to endotoxaemia in experimental biliary obstruction and to determine the source of interleukin-6 (IL-6) using immunohistochemistry. Methodology Male Wistar rats were randomized into three groups: bile duct ligation (BDL), sham operation, and control groups. They were weighed before surgery and after 1 week. On day 8, hepatic perfusion was performed with endotoxin (Escherichia coli 0111:B4). Serial samples of blood, effluent, and influent perfusate were analyzed for proinflammatory and anti-inflammatory cytokines. Ultrastructural assessment of sections of the liver was performed. Results BDL animals lost weight in the first week compared with the sham and the control animals that gained weight. Liver function tests were elevated in the BDL group. Effluent biochemistry did not reveal liver injury as a result of perfusion. Ultrastructurally, there was no evidence of liver injury, with only active Kupffer cells, preservation of liver architecture, and minimal liver injury being detected. Serum tumor necrosis factor-&agr; was not detected in any group before perfusion; however, serum IL-6 was higher in the BDL group. Portal endotoxaemia resulted in an increase in tumor necrosis factor-&agr;, IL-6, and IL-10 in the BDL group. Fluorescence immunohistochemistry demonstrated IL-6 in the sinusoidal spaces and the cytoplasm of Kupffer cells. Conclusion There is an exaggerated proinflammatory and anti-inflammatory cytokine response to portal endotoxaemia in animals with jaundice compared with the sham group.