Publications by authors named "Femke Streijger"

43 Publications

Proteomic Portraits Reveal Evolutionarily Conserved and Divergent Responses to Spinal Cord Injury.

Mol Cell Proteomics 2021 Jun 12;20:100096. Epub 2021 Jun 12.

Division of Neurosurgery, University of British Columbia, Vancouver, British Columbia, Canada.

Despite the emergence of promising therapeutic approaches in preclinical studies, the failure of large-scale clinical trials leaves clinicians without effective treatments for acute spinal cord injury (SCI). These trials are hindered by their reliance on detailed neurological examinations to establish outcomes, which inflate the time and resources required for completion. Moreover, therapeutic development takes place in animal models whose relevance to human injury remains unclear. Here, we address these challenges through targeted proteomic analyses of cerebrospinal fluid and serum samples from 111 patients with acute SCI and, in parallel, a large animal (porcine) model of SCI. We develop protein biomarkers of injury severity and recovery, including a prognostic model of neurological improvement at 6 months with an area under the receiver operating characteristic curve of 0.91, and validate these in an independent cohort. Through cross-species proteomic analyses, we dissect evolutionarily conserved and divergent aspects of the SCI response and establish the cerebrospinal fluid abundance of glial fibrillary acidic protein as a biochemical outcome measure in both humans and pigs. Our work opens up new avenues to catalyze translation by facilitating the evaluation of novel SCI therapies, while also providing a resource from which to direct future preclinical efforts.
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http://dx.doi.org/10.1016/j.mcpro.2021.100096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260874PMC
June 2021

Duraplasty in Traumatic Thoracic Spinal Cord Injury: Impact on Spinal Cord Hemodynamics, Tissue Metabolism, Histology, and Behavioral Recovery Using a Porcine Model.

J Neurotrauma 2021 Jun 18. Epub 2021 Jun 18.

International Collaboration on Repair Discoveries, University of British Columbia (UBC), Vancouver, British Columbia, Canada.

After acute traumatic spinal cord injury (SCI), the spinal cord can swell to fill the subarachnoid space and become compressed by the surrounding dura. In a porcine model of SCI, we performed a duraplasty to expand the subarachnoid space around the injured spinal cord and evaluated how this influenced acute intraparenchymal hemodynamic and metabolic responses, in addition to histological and behavioral recovery. Female Yucatan pigs underwent a T10 SCI, with or without duraplasty. Using microsensors implanted into the spinal cord parenchyma, changes in blood flow (ΔSCBF), oxygenation (ΔPO), and spinal cord pressure (ΔSCP) during and after SCI were monitored, alongside metabolic responses. Behavioral recovery was tested weekly using the Porcine Injury Behavior Scale (PTIBS). Thereafter, spinal cords were harvested for tissue sparing analyses. In both duraplasty and non-animals, the ΔSCP increased ∼5 mm Hg in the first 6 h post-injury. After this, the SCP appeared to be slightly reduced in the duraplasty animals, although the group differences were not statistically significant after controlling for injury severity in terms of impact force. During the first seven days post-SCI, the ΔSCBF or ΔPO values were not different between the duraplasty and control animals. Over 12 weeks, there was no improvement in hindlimb locomotion as assessed by PTIBS scores and no reduction in tissue damage at the injury site in the duraplasty animals. In our porcine model of SCI, duraplasty did not provide any clear evidence of long-term behavioral or tissue sparing benefit after SCI.
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http://dx.doi.org/10.1089/neu.2021.0084DOI Listing
June 2021

Characterization of Cerebrospinal Fluid Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) as a Biomarker of Human Acute Traumatic Spinal Cord Injury.

J Neurotrauma 2021 May 3. Epub 2021 May 3.

International Collaboration on Repair Discoveries (ICORD), Blusson Spinal Cord Center, University of British Columbia, Vancouver, British Columbia, Canada.

A major obstacle for translational research in acute spinal cord injury (SCI) is the lack of biomarkers that can objectively stratify injury severity and predict outcome. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a neuron-specific enzyme that shows promise as a diagnostic biomarker in traumatic brain injury (TBI), but has not been studied in SCI. In this study, cerebrospinal fluid (CSF) and serum samples were collected over the first 72-96 h post-injury from 32 acute SCI patients who were followed prospectively to determine neurological outcomes at 6 months post-injury. UCH-L1 concentration was measured using the Quanterix Simoa platform (Quanterix, Billerica, MA) and correlated to injury severity, time, and neurological recovery. We found that CSF UCH-L1 was significantly elevated by 10- to 100-fold over laminectomy controls in an injury severity- and time-dependent manner. Twenty-four-hour post-injury CSF UCH-L1 concentrations distinguished between American Spinal Injury Association Impairment Scale (AIS) A and AIS B, and AIS A and AIS C patients in the acute setting, and predicted who would remain "motor complete" (AIS A/B) at 6 months with a sensitivity of 100% and a specificity of 86%. AIS A patients who did not improve their AIS grade at 6 months post-injury were characterized by sustained elevations in CSF UCH-L1 up to 96 h. Similarly, the failure to gain >8 points on the total motor score at 6 months post-injury was associated with higher 24-h CSF UCH-L1. Unfortunately, serum UCH-L1 levels were not informative about injury severity or outcome. In conclusion, CSF UCH-L1 in acute SCI shows promise as a biomarker to reflect injury severity and predict outcome.
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http://dx.doi.org/10.1089/neu.2020.7352DOI Listing
May 2021

Characterization of Lower Urinary Tract Dysfunction after Thoracic Spinal Cord Injury in Yucatan Minipigs.

J Neurotrauma 2021 May 2;38(9):1306-1326. Epub 2021 Mar 2.

International Collaboration on Repair Discoveries (ICORD), Departments of Department of Orthopaedics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

There is an increasing need to develop approaches that will not only improve the clinical management of neurogenic lower urinary tract dysfunction (NLUTD) after spinal cord injury (SCI), but also advance therapeutic interventions aimed at recovering bladder function. Although pre-clinical research frequently employs rodent SCI models, large animals such as the pig may play an important translational role in facilitating the development of devices or treatments. Therefore, the objective of this study was to develop a urodynamics protocol to characterize NLUTD in a porcine model of SCI. An iterative process to develop the protocol to perform urodynamics in female Yucatan minipigs began with a group of spinally intact, anesthetized pigs. Subsequently, urodynamic studies were performed in a group of awake, lightly restrained pigs, before and after a contusion-compression SCI at the T2 or T9-T11 spinal cord level. Bladder tissue was obtained for histological analysis at the end of the study. All anesthetized pigs had bladders that were acontractile, which resulted in overflow incontinence once capacity was reached. Uninjured, conscious pigs demonstrated appropriate relaxation and contraction of the external urethral sphincter during the voiding phase. SCI pigs demonstrated neurogenic detrusor overactivity and a significantly elevated post-void residual volume. Relative to the control, SCI bladders were heavier and thicker. The developed urodynamics protocol allows for repetitive evaluation of lower urinary tract function in pigs at different time points post-SCI. This technique manifests the potential for using the pig as an intermediary, large animal model for translational studies in NLUTD.
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http://dx.doi.org/10.1089/neu.2020.7404DOI Listing
May 2021

Cardio-centric hemodynamic management improves spinal cord oxygenation and mitigates hemorrhage in acute spinal cord injury.

Nat Commun 2020 10 15;11(1):5209. Epub 2020 Oct 15.

International Collaboration On Repair Discoveries (ICORD), University of British Columbia, Vancouver, BC, Canada.

Chronic high-thoracic and cervical spinal cord injury (SCI) results in a complex phenotype of cardiovascular consequences, including impaired left ventricular (LV) contractility. Here, we aim to determine whether such dysfunction manifests immediately post-injury, and if so, whether correcting impaired contractility can improve spinal cord oxygenation (SCO), blood flow (SCBF) and metabolism. Using a porcine model of T2 SCI, we assess LV end-systolic elastance (contractility) via invasive pressure-volume catheterization, monitor intraparenchymal SCO and SCBF with fiberoptic oxygen sensors and laser-Doppler flowmetry, respectively, and quantify spinal cord metabolites with microdialysis. We demonstrate that high-thoracic SCI acutely impairs cardiac contractility and substantially reduces SCO and SCBF within the first hours post-injury. Utilizing the same model, we next show that augmenting LV contractility with the β-agonist dobutamine increases SCO and SCBF more effectively than vasopressor therapy, whilst also mitigating increased anaerobic metabolism and hemorrhage in the injured cord. Finally, in pigs with T2 SCI survived for 12 weeks post-injury, we confirm that acute hemodynamic management with dobutamine appears to preserve cardiac function and improve hemodynamic outcomes in the chronic setting. Our data support that cardio-centric hemodynamic management represents an advantageous alternative to the current clinical standard of vasopressor therapy for acute traumatic SCI.
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http://dx.doi.org/10.1038/s41467-020-18905-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562705PMC
October 2020

Continuous Optical Monitoring of Spinal Cord Oxygenation and Hemodynamics during the First Seven Days Post-Injury in a Porcine Model of Acute Spinal Cord Injury.

J Neurotrauma 2020 11 17;37(21):2292-2301. Epub 2020 Aug 17.

International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, British Columbia, Canada.

One of the only currently available treatment options to potentially improve neurological recovery after acute spinal cord injury (SCI) is augmentation of mean arterial blood pressure (MAP) to promote blood flow and oxygen delivery to the injured cord. However, to optimize such hemodynamic management, clinicians require a method to monitor the physiological effects of these MAP alterations within the injured cord. Therefore, we investigated the feasibility and effectiveness of using a novel optical sensor, based on near-infrared spectroscopy (NIRS), to monitor real-time spinal cord oxygenation and hemodynamics during the first 7 days post-injury in a porcine model of acute SCI. Six Yucatan miniature pigs underwent a T10 vertebral level contusion-compression injury. Spinal cord oxygenation and hemodynamics were continuously monitored by a minimally invasive custom-made NIRS sensor, and by invasive intraparenchymal (IP) probes to validate the NIRS measures. Episodes of MAP alteration and hypoxia were performed acutely after injury, and at 2 and 7 days post-injury to simulate the types of hemodynamic changes SCI patients experience after injury. The NIRS sensor demonstrated the ability to provide oxygenation and hemodynamic measurements over the 7-day post-SCI period. NIRS measures showed statistically significant correlations with each of the invasive IP measures and MAP changes during episodes of MAP alteration and hypoxia throughout the first week post-injury ( < 0.05). These results indicate that this novel NIRS system can monitor real-time changes in spinal cord oxygenation and hemodynamics over the first 7 days post-injury, and has the ability to detect local tissue changes that are reflective of systemic hemodynamic changes.
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http://dx.doi.org/10.1089/neu.2020.7086DOI Listing
November 2020

Treadmill-Based Gait Kinematics in the Yucatan Mini Pig.

J Neurotrauma 2020 11 10;37(21):2277-2291. Epub 2020 Aug 10.

Department of Neurological Surgery and Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky, USA.

Yucatan miniature pigs (YMPs) are similar to humans in spinal cord size as well as physiological and neuroanatomical features, making them a useful model for human spinal cord injury. However, little is known regarding pig gait kinematics, especially on a treadmill. In this study, 12 healthy YMPs were assessed during bipedal and/or quadrupedal stepping on a treadmill at six speeds (1.0, 1.5, 2.0, 2.5, 3.0, and 3.5 km/h). Kinematic parameters, including limb coordination and proximal and distal limb angles, were measured. Findings indicate that YMPs use a lateral sequence footfall pattern across all speeds. Stride and stance durations decreased with increasing speed whereas swing duration showed no significant change. Across all speeds assessed, no significant differences were noted between hindlimb stepping parameters for bipedal or quadrupedal gait with the exception of distal limb angular kinematics. Specifically, significant differences were observed between locomotor tasks during maximum flexion (quadrupedal > bipedal), total excursion (bipedal > quadrupedal), and the phase relationship between the timing of maximum extension between the right and left hindlimbs (bipedal > quadrupedal). Speed also impacted maximum flexion and right-left phase relationships given that significant differences were found between the fastest speed (3.5 km/h) relative to each of the other speeds. This study establishes a methodology for bipedal and quadrupedal treadmill-based kinematic testing in healthy YMPs. The treadmill approach used was effective in recruiting primarily the spinal circuitry responsible for the basic stepping patterns as has been shown in cats. We recommend 2.5 km/h (0.7 m/sec) as a target walking gait for pre-clinical studies using YMPs, which is similar to that used in cats.
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http://dx.doi.org/10.1089/neu.2020.7050DOI Listing
November 2020

Relationship between Early Vasopressor Administration and Spinal Cord Hemorrhage in a Porcine Model of Acute Traumatic Spinal Cord Injury.

J Neurotrauma 2020 08 8;37(15):1696-1707. Epub 2020 May 8.

International Collaboration on Repair Discoveries, Department of Orthopedics, The University of British Columbia, Vancouver, British Columbia, Canada.

Current practice guidelines for acute spinal cord injury (SCI) recommend augmenting mean arterial blood pressure (MAP) for the first 7 days post-injury. After SCI, the cord may be compressed by the bone/ligaments of the spinal column, limiting regional spinal cord blood flow. Following surgical decompression, blood flow may be restored, and can potentially promote a "reperfusion" injury. The effects of MAP augmentation on the injured cord during the compressed and decompressed conditions have not been previously characterized. Here, we used our porcine model of SCI to examine the impact of MAP augmentation on blood flow, oxygenation, hydrostatic pressure, metabolism, and intraparenchymal (IP) hemorrhage within the compressed and then subsequently decompressed spinal cord. Yucatan mini-pigs underwent a T10 contusion injury followed by 2 h of sustained compression. MAP augmentation of ∼20 mm Hg was achieved with norepinephrine (NE). Animals received MAP augmentation either during the period of cord compression (CP), after decompression (DCP), or during both periods (CP-DCP). Probes to monitor spinal cord blood flow (SCBF), oxygenation, pressure, and metabolic responses were inserted into the cord parenchyma adjacent to the injury site to measure these responses. The cord was harvested for histological evaluation. MAP augmentation increased SCBF and oxygenation in all groups. In the CP-DCP group, spinal cord pressure steadily increased and histological analysis showed significantly increased hemorrhage in the spinal cord at and near the injury site. MAP augmentation with vasopressors may improve blood flow and reduce ischemia in the injured cord but may also induce undesirable increases in IP pressure and hemorrhage.
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http://dx.doi.org/10.1089/neu.2019.6781DOI Listing
August 2020

A porcine model for studying the cardiovascular consequences of high-thoracic spinal cord injury.

J Physiol 2020 03 11;598(5):929-942. Epub 2020 Feb 11.

International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, Canada.

Key Points: We have developed a novel porcine model of high-thoracic midline contusion spinal cord injury (SCI) at the T2 spinal level. We describe this model and the ensuing cardiovascular and neurohormonal responses, and demonstrate the model is efficacious for studying clinically relevant cardiovascular dysfunction post-SCI. We demonstrate that the high-thoracic SCI model, but not a low-thoracic SCI model, induces persistent hypotension along with a gradual reduction in plasma noradrenaline and increases in plasma aldosterone and angiotensin II. We additionally conducted a proof-of-concept long-term (12 weeks) survival study in animals with T2 contusion SCI demonstrating the potential utility of this model for not only acute experimentation but also long-term drug studies prior to translation to the clinic.

Abstract: Cardiovascular disease is a leading cause of morbidity and mortality in the spinal cord injury (SCI) population, especially in those with high-thoracic or cervical SCI. With this in mind, we aimed to develop a large animal (porcine) model of high-thoracic (T2 level) contusion SCI and compare the haemodynamic and neurohormonal responses of this injury against a low-thoracic (T10 level) model. Ten Yorkshire pigs were randomly subjected to 20 cm weight drop contusion SCI at either the T2 or the T10 spinal level. Systolic blood pressure (SBP), mean arterial pressure (MAP) and heart rate (HR) were continuously monitored until 4 h post-SCI. Plasma noradrenaline (NA), aldosterone and angiotensin II (ANGII) were measured pre-SCI and at 30, 60, 120 and 240 min post-SCI. Additionally, two Yucatan pigs were subjected to T2-SCI and survived up to 12 weeks post-injury to demonstrate the efficacy of this model for long-term survival studies. Immediately after T2-SCI, SBP, MAP and HR increased (P < 0.0001). Between decompression (5 min post-SCI) and 30 min post-decompression in T2-SCI, SBP and MAP were lower than pre-SCI (P < 0.038). At 3 and 4 h after T2-SCI, SBP remained lower than pre-SCI (P = 0.048). After T10-SCI, haemodynamic indices remained largely unaffected. Plasma NA was lower in T2- vs. T10-SCI post-SCI, whilst aldosterone and ANGII were higher. Both chronically injured pigs demonstrated a vast reduction in SBP at 12 weeks post-SCI. Our model of T2-SCI causes a rapid and sustained alteration in neurohormonal control and cardiovascular function, which does not occur in the T10 model.
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http://dx.doi.org/10.1113/JP278451DOI Listing
March 2020

Optical Assessment of Spinal Cord Tissue Oxygenation Using a Miniaturized Near Infrared Spectroscopy Sensor.

J Neurotrauma 2019 11 17;36(21):3034-3043. Epub 2019 Jun 17.

Department of Orthopaedics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

Despite advances in the treatment of acute spinal cord injury (SCI), measures to mitigate permanent neurological deficits in affected patients are limited. Immediate post-trauma hemodynamic management of patients, to maintain blood supply and improve oxygenation to the injured spinal cord, is currently one aspect of critical care which clinicians can utilize to improve neurological outcomes. However, without a way to monitor the response of spinal cord hemodynamics and oxygenation in real time, optimizing hemodynamic management is challenging and limited in scope. This study aims to investigate the feasibility and validity of using a miniaturized multi-wavelength near-infrared spectroscopy (NIRS) sensor for direct transdural monitoring of spinal cord oxygenation in an animal model of acute SCI. Nine Yorkshire pigs underwent a weight-drop T10 contusion-compression injury and received episodes of ventilatory hypoxia and alterations in mean arterial pressure (MAP). Spinal cord hemodynamics and oxygenation were monitored throughout by a non-invasive transdural NIRS sensor, as well as an invasive intraparenchymal sensor as a comparison. NIRS parameters of tissue oxygenation were highly correlated with intraparenchymal measures of tissue oxygenation. In particular, during periods of hypoxia and MAP alterations, changes of NIRS-derived spinal cord oxygenated hemoglobin and tissue oxygenation percentage corresponded well with the changes in spinal cord oxygen partial pressures measured by the intraparenchymal sensor. Our data confirm that during hypoxic episodes and as changes occur in the MAP, non-invasive NIRS can detect and measure real-time changes in spinal cord oxygenation with a high degree of sensitivity and specificity.
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http://dx.doi.org/10.1089/neu.2018.6208DOI Listing
November 2019

MicroRNA Biomarkers in Cerebrospinal Fluid and Serum Reflect Injury Severity in Human Acute Traumatic Spinal Cord Injury.

J Neurotrauma 2019 08 14;36(15):2358-2371. Epub 2019 May 14.

1International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, British Columbia, Canada.

Spinal cord injury (SCI) is a devastating condition with variability in injury mechanisms and neurologic recovery. Spinal cord impairment after SCI is measured and classified by a widely accepted standard neurological examination. In the very acute stages post-injury, however, this examination is extremely challenging (and often impossible) to conduct and has modest prognostic value in terms of neurological recovery. The lack of objective tools to classify injury severity and predict outcome is a barrier for clinical trials and thwarts development of therapies for those with SCI. Biological markers (biomarkers) represent a promising, complementary approach to these challenges because they represent an unbiased approach to classify injury severity and predict neurological outcome. Identification of a suitable panel of molecular biomarkers would comprise a fundamental shift in how patients with acute SCI are evaluated, stratified, and treated in clinical trials. MicroRNA are attractive biomarker candidates in neurological disorders for several reasons, including their stability in biological fluids, their conservation between humans and model mammals, and their tissue specificity. In this study, we used next-generation sequencing to identify microRNA associated with injury severity within the cerebrospinal fluid (CSF) and serum of human patients with acute SCI. The CSF and serum samples were obtained 1-5 days post-injury from 39 patients with acute SCI (24 American Spinal Injury Association Impairment Scale [AIS] A, 8 AIS B, 7 AIS C) and from five non-SCI controls. We identified a severity-dependent pattern of change in microRNA expression in CSF and identified a set of microRNA that are diagnostic of baseline AIS classification and prognostic of neurological outcome six months post-injury. The data presented here provide a comprehensive description of the CSF and serum microRNA expression changes that occur after acute human SCI. This data set reveals microRNA candidates that warrant further evaluation as biomarkers of injury severity after SCI and as key regulators in other neurological disorders.
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http://dx.doi.org/10.1089/neu.2018.6256DOI Listing
August 2019

Differences in Morphometric Measures of the Uninjured Porcine Spinal Cord and Dural Sac Predict Histological and Behavioral Outcomes after Traumatic Spinal Cord Injury.

J Neurotrauma 2019 11 23;36(21):3005-3017. Epub 2019 May 23.

International Collaboration on Repair Discoveries (ICORD), Department of Orthopaedics, University of British Columbia (UBC), Vancouver, British Columbia, Canada.

One of the challenges associated with conducting experiments in animal models of traumatic spinal cord injury (SCI) is inducing a consistent injury with minimal variability in the degree of tissue damage and resultant behavioral and biochemical outcomes. We evaluated how the variability in morphometry of the spinal cord and surrounding cerebrospinal fluid (CSF) contributes to the variability in behavioral and histological outcomes in our porcine model of SCI. Using intraoperative ultrasound imaging, spinal cord morphometry was assessed in seven Yucatan minipigs undergoing a weight-drop T10 contusion-compression injury. Bivariate and multi-variate analysis and modeling were used to identify native morphometrical determinants of interanimal variability in histological and behavioral outcomes. The measured biomechanical impact parameters did not correlate with the histological measures or hindlimb locomotor behavior (Porcine Thoracic Injury Behavior Scale). In contrast, clear associations were revealed between CSF layer morphometry and the amount of white matter and tissue sparing. Specifically, the dorsoventral diameter of the dural sac and ventral CSF space were strong predictors of behavioral and histological outcome and together explained ≥95.0% of the variance in these parameters. In addition, a dorsoventral diameter of the spinal cord less than 5.331 mm was a strong contributing factor to poor behavioral recovery over 12 weeks. These results indicate that interanimal variability in cord morphometry provides a potential biological explanation for the observed heterogeneity in histological and behavioral outcomes. Such knowledge is helpful for appropriately balancing experimental groups, and/or varying impact parameters to match cord and CSF layer dimensions for future studies.
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http://dx.doi.org/10.1089/neu.2018.5930DOI Listing
November 2019

Sensorimotor plasticity after spinal cord injury: a longitudinal and translational study.

Ann Clin Transl Neurol 2019 01 1;6(1):68-82. Epub 2018 Dec 1.

ICORD University of British Columbia Vancouver British Columbia Canada.

Objective: The objective was to track and compare the progression of neuroplastic changes in a large animal model and humans with spinal cord injury.

Methods: A total of 37 individuals with acute traumatic spinal cord injury were followed over time (1, 3, 6, and 12 months post-injury) with repeated neurophysiological assessments. Somatosensory and motor evoked potentials were recorded in the upper extremities above the level of injury. In a reverse-translational approach, similar neurophysiological techniques were examined in a porcine model of thoracic spinal cord injury. Twelve Yucatan mini-pigs underwent a contusive spinal cord injury at T10 and tracked with somatosensory and motor evoked potentials assessments in the fore- and hind limbs pre- (baseline, post-laminectomy) and post-injury (10 min, 3 h, 12 weeks).

Results: In both humans and pigs, the sensory responses in the cranial coordinates of upper extremities/forelimbs progressively increased from immediately post-injury to later time points. Motor responses in the forelimbs increased immediately after experimental injury in pigs, remaining elevated at 12 weeks. In humans, motor evoked potentials were significantly higher at 1-month (and remained so at 1 year) compared to normative values.

Conclusions: Despite notable differences between experimental models and the human condition, the brain's response to spinal cord injury is remarkably similar between humans and pigs. Our findings further underscore the utility of this large animal model in translational spinal cord injury research.
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http://dx.doi.org/10.1002/acn3.679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331953PMC
January 2019

Review of the UBC Porcine Model of Traumatic Spinal Cord Injury.

J Korean Neurosurg Soc 2018 Sep 31;61(5):539-547. Epub 2018 Aug 31.

International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, Canada.

Traumatic spinal cord injury (SCI) research has recently focused on the use of rat and mouse models for in vivo SCI experiments. Such small rodent SCI models are invaluable for the field, and much has been discovered about the biologic and physiologic aspects of SCI from these models. It has been difficult, however, to reproduce the efficacy of treatments found to produce neurologic benefits in rodent SCI models when these treatments are tested in human clinical trials. A large animal model may have advantages for translational research where anatomical, physiological, or genetic similarities to humans may be more relevant for pre-clinically evaluating novel therapies. Here, we review the work carried out at the University of British Columbia (UBC) on a large animal model of SCI that utilizes Yucatan miniature pigs. The UBC porcine model of SCI may be a useful intermediary in the pre-clinical testing of novel pharmacological treatments, cell-based therapies, and the "bedside back to bench" translation of human clinical observations, which require preclinical testing in an applicable animal model.
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http://dx.doi.org/10.3340/jkns.2017.0276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129752PMC
September 2018

A Direct Comparison between Norepinephrine and Phenylephrine for Augmenting Spinal Cord Perfusion in a Porcine Model of Spinal Cord Injury.

J Neurotrauma 2018 06 28;35(12):1345-1357. Epub 2018 Mar 28.

1 International Collaboration on Repair Discoveries, University of British Columbia (UBC) , Vancouver, British Columbia, Canada .

Current clinical guidelines recommend elevating the mean arterial blood pressure (MAP) to increase spinal cord perfusion in patients with acute spinal cord injury (SCI). This is typically achieved with vasopressors such as norepinephrine (NE) and phenylephrine (PE). These drugs differ in their pharmacological properties and potentially have different effects on spinal cord blood flow (SCBF), oxygenation (PO), and downstream metabolism after injury. Using a porcine model of thoracic SCI, we evaluated how these vasopressors influenced intraparenchymal SCBF, PO, hydrostatic pressure, and metabolism within the spinal cord adjacent to the injury site. Yorkshire pigs underwent a contusion/compression SCI at T10 and were randomized to receive either NE or PE for MAP elevation of 20 mm Hg, or no MAP augmentation. Prior to injury, a combined SCBF/PO sensor, a pressure sensor, and a microdialysis probe were inserted into the spinal cord adjacent to T10 at two locations: a "proximal" site and a "distal" site, 2 mm and 22 mm from the SCI, respectively. At the proximal site, NE and PE resulted in little improvement in SCBF during cord compression. Following decompression, NE resulted in increased SCBF and PO, whereas decreased levels were observed for PE. However, both NE and PE were associated with a gradual decrease in the lactate to pyruvate (L/P) ratio after decompression. PE was associated with greater hemorrhage through the injury site than that in control animals. Combined, our results suggest that NE promotes better restoration of blood flow and oxygenation than PE in the traumatically injured spinal cord, thus providing a physiological rationale for selecting NE over PE in the hemodynamic management of acute SCI.
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http://dx.doi.org/10.1089/neu.2017.5285DOI Listing
June 2018

Comparison of in vivo and ex vivo viscoelastic behavior of the spinal cord.

Acta Biomater 2018 03 26;68:78-89. Epub 2017 Dec 26.

School of Biomedical Engineering, Colorado State University, Fort Collins, CO, USA; Department of Mechanical Engineering, Colorado State University, Fort Collins, CO, USA; Department of Clinical Sciences, Colorado State University, Fort Collins, CO, USA. Electronic address:

Despite efforts to simulate the in vivo environment, post-mortem degradation and lack of blood perfusion complicate the use of ex vivo derived material models in computational studies of spinal cord injury. In order to quantify the mechanical changes that manifest ex vivo, the viscoelastic behavior of in vivo and ex vivo porcine spinal cord samples were compared. Stress-relaxation data from each condition were fit to a non-linear viscoelastic model using a novel characterization technique called the direct fit method. To validate the presented material models, the parameters obtained for each condition were used to predict the respective dynamic cyclic response. Both ex vivo and in vivo samples displayed non-linear viscoelastic behavior with a significant increase in relaxation with applied strain. However, at all three strain magnitudes compared, ex vivo samples experienced a higher stress and greater relaxation than in vivo samples. Significant differences between model parameters also showed distinct relaxation behaviors, especially in non-linear relaxation modulus components associated with the short-term response (0.1-1 s). The results of this study underscore the necessity of utilizing material models developed from in vivo experimental data for studies of spinal cord injury, where the time-dependent properties are critical. The ability of each material model to accurately predict the dynamic cyclic response validates the presented methodology and supports the use of the in vivo model in future high-resolution finite element modeling efforts.

Statement Of Significance: Neural tissues (such as the brain and spinal cord) display time-dependent, or viscoelastic, mechanical behavior making it difficult to model how they respond to various loading conditions, including injury. Methods that aim to characterize the behavior of the spinal cord almost exclusively use ex vivo cadaveric or animal samples, despite evidence that time after death affects the behavior compared to that in a living animal (in vivo response). Therefore, this study directly compared the mechanical response of ex vivo and in vivo samples to quantify these differences for the first time. This will allow researchers to draw more accurate conclusions about spinal cord injuries based on ex vivo data (which are easier to obtain) and emphasizes the importance of future in vivo experimental animal work.
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http://dx.doi.org/10.1016/j.actbio.2017.12.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803400PMC
March 2018

Changes in Pressure, Hemodynamics, and Metabolism within the Spinal Cord during the First 7 Days after Injury Using a Porcine Model.

J Neurotrauma 2017 12 14;34(24):3336-3350. Epub 2017 Sep 14.

1 International Collaboration on Repair Discoveries (ICORD), University of British Columbia , Vancouver, British Columbia, Canada .

Traumatic spinal cord injury (SCI) triggers many perturbations within the injured cord, such as decreased perfusion, reduced tissue oxygenation, increased hydrostatic pressure, and disrupted bioenergetics. While much attention is directed to neuroprotective interventions that might alleviate these early pathophysiologic responses to traumatic injury, the temporo-spatial characteristics of these responses within the injured cord are not well documented. In this study, we utilized our Yucatan mini-pig model of traumatic SCI to characterize intraparenchymal hemodynamic and metabolic changes within the spinal cord for 1 week post-injury. Animals were subjected to a contusion/compression SCI at T10. Prior to injury, probes for microdialysis and the measurement of spinal cord blood flow (SCBF), oxygenation (in partial pressure of oxygen; PaPO), and hydrostatic pressure were inserted into the spinal cord 0.2 and 2.2 cm from the injury site. Measurements occurred under anesthesia for 4 h post-injury, after which the animals were recovered and measurements continued for 7 days. Close to the lesion (0.2 cm), SCBF levels decreased immediately after SCI, followed by an increase in the subsequent days. Similarly, PaPO plummeted, where levels remained diminished for up to 7 days post-injury. Lactate/pyruvate (L/P) ratio increased within minutes. Further away from the injury site (2.2 cm), L/P ratio also gradually increased. Hydrostatic pressure remained consistently elevated for days and negatively correlated with changes in SCBF. An imbalance between SCBF and tissue metabolism also was observed, resulting in metabolic stress and insufficient oxygen levels. Taken together, traumatic SCI resulted in an expanding area of ischemia/hypoxia, with ongoing physiological perturbations sustained out to 7 days post-injury. This suggests that our clinical practice of hemodynamically supporting patients out to 7 days post-injury may fail to address persistent ischemia within the injured cord. A detailed understanding of these pathophysiological mechanisms after SCI is essential to promote best practices for acute SCI patients.
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http://dx.doi.org/10.1089/neu.2017.5034DOI Listing
December 2017

Serum MicroRNAs Reflect Injury Severity in a Large Animal Model of Thoracic Spinal Cord Injury.

Sci Rep 2017 05 3;7(1):1376. Epub 2017 May 3.

International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, British Columbia, Canada.

Therapeutic development for spinal cord injury is hindered by the difficulty in conducting clinical trials, which to date have relied solely on functional outcome measures for patient enrollment, stratification, and evaluation. Biological biomarkers that accurately classify injury severity and predict neurologic outcome would represent a paradigm shift in the way spinal cord injury clinical trials could be conducted. MicroRNAs have emerged as attractive biomarker candidates due to their stability in biological fluids, their phylogenetic similarities, and their tissue specificity. Here we characterized a porcine model of spinal cord injury using a combined behavioural, histological, and molecular approach. We performed next-generation sequencing on microRNAs in serum samples collected before injury and then at 1, 3, and 5 days post injury. We identified 58, 21, 9, and 7 altered miRNA after severe, moderate, and mild spinal cord injury, and SHAM surgery, respectively. These data were combined with behavioural and histological analysis. Overall miRNA expression at 1 and 3 days post injury strongly correlates with outcome measures at 12 weeks post injury. The data presented here indicate that serum miRNAs are promising candidates as biomarkers for the evaluation of injury severity for spinal cord injury or other forms of traumatic, acute, neurologic injury.
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http://dx.doi.org/10.1038/s41598-017-01299-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431108PMC
May 2017

A Targeted Proteomics Analysis of Cerebrospinal Fluid after Acute Human Spinal Cord Injury.

J Neurotrauma 2017 06 7;34(12):2054-2068. Epub 2017 Apr 7.

1 International Collaboration on Repair Discoveries (ICORD), Blusson Spinal Cord Centre, University of British Columbia , Vancouver, British Columbia, Canada .

Efforts to validate novel therapies in acute clinical trials for spinal cord injury (SCI) are impeded by the lack of objective quantitative measures that reflect injury severity and accurately predict neurological recovery. Therefore, a strong rationale exists for establishing neurochemical biomarkers that objectively quantify injury severity and predict outcome. Here, we conducted a targeted proteomics analysis of cerebrospinal fluid (CSF) samples derived from 29 acute SCI patients (American Spinal Injury Association Impairment Scale [AIS] A, B, or C) acquired at 24, 48, and 72 h post-injury. From a total of 165 proteins, we identified 27 potential biomarkers of injury severity (baseline AIS A, B, or C), with triosephosphate isomerase having the strongest relationship to AIS grade. The majority of affected proteins (24 of 27) were more abundant in samples from AIS A patients than in those from AIS C patients, suggesting that for the most part, these proteins are released into the CSF more readily with more severe trauma to the spinal cord. We then analyzed the relationship between CSF protein abundance and neurological recovery. For AIS grade improvement over 6 months, we identified 34 proteins that were associated with AIS grade conversion (p < 0.05); however, these associations were not statistically significant after adjusting for multiple comparisons. For total motor score (TMS) recovery over 6 months, after adjusting for baseline neurological injury level, we identified 46 proteins with a statistically significant association with TMS recovery. Twenty-two of these proteins were among the 27 proteins that were related to baseline AIS grade, consistent with the notion that protein markers that reflect a more severe injury also appropriately predict a poorer recovery of motor function. In summary, this study provides a description of the CSF proteome changes that occur after acute human SCI, and reveals a number of protein candidates for further validation as potential biomarkers of injury severity.
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http://dx.doi.org/10.1089/neu.2016.4879DOI Listing
June 2017

Parallel Metabolomic Profiling of Cerebrospinal Fluid and Serum for Identifying Biomarkers of Injury Severity after Acute Human Spinal Cord Injury.

Sci Rep 2016 12 14;6:38718. Epub 2016 Dec 14.

Department of Chemistry, University of Alberta, Edmonton, AB, T6G2G2, Canada.

Suffering an acute spinal cord injury (SCI) can result in catastrophic physical and emotional loss. Efforts to translate novel therapies in acute clinical trials are impeded by the SCI community's singular dependence upon functional outcome measures. Therefore, a compelling rationale exists to establish neurochemical biomarkers for the objective classification of injury severity. In this study, CSF and serum samples were obtained at 3 time points (~24, 48, and 72 hours post-injury) from 30 acute SCI patients (10 AIS A, 12 AIS B, and 8 AIS C). A differential chemical isotope labeling liquid chromatography mass spectrometry (CIL LC-MS) with a universal metabolome standard (UMS) was applied to the metabolomic profiling of these samples. This method provided enhanced detection of the amine- and phenol-containing submetabolome. Metabolic pathway analysis revealed dysregulations in arginine-proline metabolism following SCI. Six CSF metabolites were identified as potential biomarkers of baseline injury severity, and good classification performance (AUC > 0.869) was achieved by using combinations of these metabolites in pair-wise comparisons of AIS A, B and C patients. Using the UMS strategy, the current data set can be expanded to a larger cohort for biomarker validation, as well as discovering biomarkers for predicting neurologic outcome.
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http://dx.doi.org/10.1038/srep38718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155264PMC
December 2016

Cerebrospinal Fluid Biomarkers To Stratify Injury Severity and Predict Outcome in Human Traumatic Spinal Cord Injury.

J Neurotrauma 2017 02 15;34(3):567-580. Epub 2016 Aug 15.

1 Department of Orthopedics, Vancouver Spine Surgery Institute , Vancouver, British Columbia, Canada .

Neurologic impairment after spinal cord injury (SCI) is currently measured and classified by functional examination. Biological markers that objectively classify injury severity and predict outcome would greatly facilitate efforts to evaluate acute SCI therapies. The purpose of this study was to determine how well inflammatory and structural proteins within the cerebrospinal fluid (CSF) of acute traumatic SCI patients predicted American Spinal Injury Association Impairment Scale (AIS) grade conversion and motor score improvement over 6 months. Fifty acute SCI patients (29 AIS A, 9 AIS B, 12 AIS C; 32 cervical, 18 thoracic) were enrolled and CSF obtained through lumbar intrathecal catheters to analyze interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1, tau, S100β, and glial fibrillary acidic protein (GFAP) at 24 h post-injury. The levels of IL-6, tau, S100β, and GFAP were significantly different between patients with baseline AIS grades of A, B, or C. The levels of all proteins (IL-6, IL-8, MCP-1, tau, S100β, and GFAP) were significantly different between those who improved an AIS grade over 6 months and those who did not improve. Linear discriminant analysis modeling was 83% accurate in predicting AIS conversion. For AIS A patients, the concentrations of proteins such as IL-6 and S100β correlated with conversion to AIS B or C. Motor score improvement also was strongly correlated with the 24-h post-injury CSF levels of all six biomarkers. The analysis of CSF can provide valuable biological information about injury severity and recovery potential after acute SCI. Such biological markers may be valuable tools for stratifying individuals in acute clinical trials where variability in spontaneous recovery requires large recruitment cohorts for sufficient power.
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http://dx.doi.org/10.1089/neu.2016.4435DOI Listing
February 2017

Responses of the Acutely Injured Spinal Cord to Vibration that Simulates Transport in Helicopters or Mine-Resistant Ambush-Protected Vehicles.

J Neurotrauma 2016 12 5;33(24):2217-2226. Epub 2016 Jul 5.

1 International Collaboration on Repair Discoveries (ICORD), University of British Columbia , Vancouver, British Columbia, Canada .

In the military environment, injured soldiers undergoing medical evacuation via helicopter or mine-resistant ambush-protected vehicle (MRAP) are subjected to vibration and shock inherent to the transport vehicle. We conducted the present study to assess the consequences of such vibration on the acutely injured spinal cord. We used a porcine model of spinal cord injury (SCI). After a T10 contusion-compression injury, animals were subjected to 1) no vibration (n = 7-8), 2) whole body vibration at frequencies and amplitudes simulating helicopter transport (n = 8), or 3) whole body vibration simulating ground transportation in an MRAP ambulance (n = 7). Hindlimb locomotor function (using Porcine Thoracic Injury Behavior Scale [PTIBS]), Eriochrome Cyanine histochemistry and biochemical analysis of inflammatory and neural damage markers were analyzed. Cerebrospinal fluid (CSF) expression levels for monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6, IL-8, and glial fibrillary acidic protein (GFAP) were similar between the helicopter or MRAP group and the unvibrated controls. Spared white/gray matter tended to be lower in the MRAP-vibrated animals than in the unvibrated controls, especially rostral to the epicenter. However, spared white/gray matter in the helicopter-vibrated group appeared normal. Although there was a relationship between the extent of sparing and the extent of locomotor recovery, no significant differences were found in PTIBS scores between the groups. In summary, exposures to vibration in the context of ground (MRAP) or aeromedical (helicopter) transportation did not significantly impair functional outcome in our large animal model of SCI. However, MRAP vibration was associated with increased tissue damage around the injury site, warranting caution around exposure to vehicle vibration acutely after SCI.
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http://dx.doi.org/10.1089/neu.2016.4456DOI Listing
December 2016

The Evaluation of Magnesium Chloride within a Polyethylene Glycol Formulation in a Porcine Model of Acute Spinal Cord Injury.

J Neurotrauma 2016 12 1;33(24):2202-2216. Epub 2016 Jun 1.

1 International Collaboration on Repair Discoveries (ICORD), University of British Columbia , Blusson Spinal Cord Center, Vancouver, British Columbia, Canada .

A porcine model of spinal cord injury (SCI) was used to evaluate the neuroprotective effects of magnesium chloride (MgCl) within a polyethylene glycol (PEG) formulation, called "AC105" (Acorda Therapeutics Inc., Ardsley, NY). Specifically, we tested the hypothesis that AC105 would lead to greater tissue sparing at the injury site and improved behavioral outcome when delivered in a clinically realistic time window post-injury. Four hours after contusion/compression injury, Yucatan minipigs were randomized to receive a 30-min intravenous infusion of AC105, magnesium sulfate (MgSO), or saline. Animals received 4 additional infusions of the same dose at 6-h intervals. Behavioral recovery was tested for 12 weeks using two-dimensional (2D) kinematics during weight-supported treadmill walking and the Porcine Injury Behavior Scale (PTIBS), a 10-point locomotion scale. Spinal cords were evaluated ex vivo by diffusion-weighted magnetic resonance imaging (MRI) and subjected to histological analysis. Treatment with AC105 or MgSO did not result in improvements in locomotor recovery on the PTIBS or in 2D kinematics on weight-supported treadmill walking. Diffusion weighted imaging (DWI) showed severe loss of tissue integrity at the impact site, with decreased fractional anisotropy and increased mean diffusivity; this was not improved with AC105 or MgSO treatment. Histological analysis revealed no significant increase in gray or white matter sparing with AC105 or MgSO treatment. Finally, AC105 did not result in higher Mg levels in CSF than with the use of standard MgSO. In summary, when testing AC105 in a porcine model of SCI, we were unable to reproduce the promising therapeutic benefits observed previously in less-severe rodent models of SCI.
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http://dx.doi.org/10.1089/neu.2016.4439DOI Listing
December 2016

Differential Histopathological and Behavioral Outcomes Eight Weeks after Rat Spinal Cord Injury by Contusion, Dislocation, and Distraction Mechanisms.

J Neurotrauma 2016 09 4;33(18):1667-84. Epub 2016 Apr 4.

1 International Collaboration on Repair Discoveries (ICORD), University of British Columbia , Vancouver, British Columbia, Canada .

The objective of this study was to compare the long-term histological and behavioral outcomes after spinal cord injury (SCI) induced by one of three distinct biomechanical mechanisms: dislocation, contusion, and distraction. Thirty male Sprague-Dawley rats were randomized to incur a traumatic cervical SCI by one of these three clinically relevant mechanisms. The injured cervical spines were surgically stabilized, and motor function was assessed for the following 8 weeks. The spinal cords were then harvested for histologic analysis. Quantification of white matter sparing using Luxol fast blue staining revealed that dislocation injury caused the greatest overall loss of white matter, both laterally and along the rostrocaudal axis of the injured cord. Distraction caused enlarged extracellular spaces and structural alteration in the white matter but spared the most myelinated axons overall. Contusion caused the most severe loss of myelinated axons in the dorsal white matter. Immunohistochemistry for the neuronal marker NeuN combined with Fluoro Nissl revealed that the dislocation mechanism resulted in the greatest neuronal cell losses in both the ventral and dorsal horns. After the distraction injury mechanism, animals displayed no recovery of grip strength over time, in contrast to the animals subjected to contusion or dislocation injuries. After the dislocation injury mechanism, animals displayed no improvement in the grooming test, in contrast to the animals subjected to contusion or distraction injuries. These data indicate that different SCI mechanisms result in distinct patterns of histopathology and behavioral recovery. Understanding this heterogeneity may be important for the future development of therapeutic interventions that target specific neuropathology after SCI.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035937PMC
http://dx.doi.org/10.1089/neu.2015.4218DOI Listing
September 2016

Large animal and primate models of spinal cord injury for the testing of novel therapies.

Exp Neurol 2015 Jul 19;269:154-68. Epub 2015 Apr 19.

University of Miami Miller School of Medicine, LPLC, 1095 NW 14 Terrace, Miami, FL 33136, USA. Electronic address:

Large animal and primate models of spinal cord injury (SCI) are being increasingly utilized for the testing of novel therapies. While these represent intermediary animal species between rodents and humans and offer the opportunity to pose unique research questions prior to clinical trials, the role that such large animal and primate models should play in the translational pipeline is unclear. In this initiative we engaged members of the SCI research community in a questionnaire and round-table focus group discussion around the use of such models. Forty-one SCI researchers from academia, industry, and granting agencies were asked to complete a questionnaire about their opinion regarding the use of large animal and primate models in the context of testing novel therapeutics. The questions centered around how large animal and primate models of SCI would be best utilized in the spectrum of preclinical testing, and how much testing in rodent models was warranted before employing these models. Further questions were posed at a focus group meeting attended by the respondents. The group generally felt that large animal and primate models of SCI serve a potentially useful role in the translational pipeline for novel therapies, and that the rational use of these models would depend on the type of therapy and specific research question being addressed. While testing within these models should not be mandatory, the detection of beneficial effects using these models lends additional support for translating a therapy to humans. These models provides an opportunity to evaluate and refine surgical procedures prior to use in humans, and safety and bio-distribution in a spinal cord more similar in size and anatomy to that of humans. Our results reveal that while many feel that these models are valuable in the testing of novel therapies, important questions remain unanswered about how they should be used and how data derived from them should be interpreted.
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http://dx.doi.org/10.1016/j.expneurol.2015.04.008DOI Listing
July 2015

The effect of whole-body resonance vibration in a porcine model of spinal cord injury.

J Neurotrauma 2015 Jun 9;32(12):908-21. Epub 2015 Apr 9.

1 International Collaboration on Repair Discoveries (ICORD), University of British Columbia , Vancouver, British Columbia, Canada .

Whole-body vibration has been identified as a potential stressor to spinal cord injury (SCI) patients during pre-hospital transportation. However, the effect that such vibration has on the acutely injured spinal cord is largely unknown, particularly in the frequency domain of 5 Hz in which resonance of the spine occurs. The objective of the study was to investigate the consequences of resonance vibration on the injured spinal cord. Using our previously characterized porcine model of SCI, we subjected animals to resonance vibration (5.7±0.46 Hz) or no vibration for a period of 1.5 or 3.0 h. Locomotor function was assessed weekly and cerebrospinal fluid (CSF) samples were collected to assess different inflammatory and injury severity markers. Spinal cords were evaluated histologically to quantify preserved white and gray matter. No significant differences were found between groups for CSF levels of monocyte chemotactic protein-1, interleukin 6 (IL-6) and lL-8. Glial fibrillary acidic protein levels were lower in the resonance vibration group, compared with the non-vibrated control group. Spared white matter tissue was increased within the vibrated group at 7 d post-injury but this difference was not apparent at the 12-week time-point. No significant difference was observed in locomotor recovery following resonance vibration of the spine. Here, we demonstrate that exposure to resonance vibration for 1.5 or 3 h following SCI in our porcine model is not detrimental to the functional or histological outcomes. Our observation that a 3.0-h period of vibration at resonance frequency induces modest histological improvement at one week post-injury warrants further study.
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http://dx.doi.org/10.1089/neu.2014.3707DOI Listing
June 2015

Ketogenic diet improves forelimb motor function after spinal cord injury in rodents.

PLoS One 2013 4;8(11):e78765. Epub 2013 Nov 4.

International Collaboration on Repair Discoveries (ICORD), Blusson Spinal Cord Center, Vancouver, British Columbia, Canada.

High fat, low carbohydrate ketogenic diets (KD) are validated non-pharmacological treatments for some forms of drug-resistant epilepsy. Ketones reduce neuronal excitation and promote neuroprotection. Here, we investigated the efficacy of KD as a treatment for acute cervical spinal cord injury (SCI) in rats. Starting 4 hours following C5 hemi-contusion injury animals were fed either a standard carbohydrate based diet or a KD formulation with lipid to carbohydrate plus protein ratio of 3:1. The forelimb functional recovery was evaluated for 14 weeks, followed by quantitative histopathology. Post-injury 3:1 KD treatment resulted in increased usage and range of motion of the affected forepaw. Furthermore, KD improved pellet retrieval with recovery of wrist and digit movements. Importantly, after returning to a standard diet after 12 weeks of KD treatment, the improved forelimb function remained stable. Histologically, the spinal cords of KD treated animals displayed smaller lesion areas and more grey matter sparing. In addition, KD treatment increased the number of glucose transporter-1 positive blood vessels in the lesion penumbra and monocarboxylate transporter-1 (MCT1) expression. Pharmacological inhibition of MCTs with 4-CIN (α-cyano-4-hydroxycinnamate) prevented the KD-induced neuroprotection after SCI, In conclusion, post-injury KD effectively promotes functional recovery and is neuroprotective after cervical SCI. These beneficial effects require the function of monocarboxylate transporters responsible for ketone uptake and link the observed neuroprotection directly to the function of ketones, which are known to exert neuroprotection by multiple mechanisms. Our data suggest that current clinical nutritional guidelines, which include relatively high carbohydrate contents, should be revisited.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078765PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817084PMC
August 2014

Nonlinear viscoelastic characterization of the porcine spinal cord.

Acta Biomater 2014 Feb 7;10(2):792-7. Epub 2013 Nov 7.

Department of Mechanical Engineering, Colorado State University, Fort Collins, CO, USA; School of Biomedical Engineering, Colorado State University, Fort Collins, CO, USA; Department of Clinical Sciences, Colorado State University, Fort Collins, CO, USA. Electronic address:

Although quasi-static and quasi-linear viscoelastic properties of the spinal cord have been reported previously, there are no published studies that have investigated the fully (strain-dependent) nonlinear viscoelastic properties of the spinal cord. In this study, stress relaxation experiments and dynamic cycling were performed on six fresh porcine lumbar cord specimens to examine their viscoelastic mechanical properties. The stress relaxation data were fitted to a modified superposition formulation and a novel finite ramp time correction technique was applied. The parameters obtained from this fitting methodology were used to predict the average dynamic cyclic viscoelastic behavior of the porcine cord. The data indicate that the porcine spinal cord exhibited fully nonlinear viscoelastic behavior. The average weighted root mean squared error for a Heaviside ramp fit was 2.8 kPa, which was significantly greater (p<0.001) than that of the nonlinear (comprehensive viscoelastic characterization method) fit (0.365 kPa). Further, the nonlinear mechanical parameters obtained were able to accurately predict the dynamic behavior, thus exemplifying the reliability of the obtained nonlinear parameters. These parameters will be important for future studies investigating various damage mechanisms of the spinal cord and studies developing high-resolution finite elements models of the spine.
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http://dx.doi.org/10.1016/j.actbio.2013.10.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059047PMC
February 2014

Intraparenchymal microdialysis after acute spinal cord injury reveals differential metabolic responses to contusive versus compressive mechanisms of injury.

J Neurotrauma 2013 Sep 9;30(18):1564-76. Epub 2013 Aug 9.

International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, Canada.

In animal models, spinal cord injury (SCI) is typically imparted by contusion alone (e.g., weight drop) or by compression alone (e.g., clip compression). In humans, however, the cord is typically injured by a combination of violent contusion followed by varying degrees of ongoing mechanical compression. Understanding how the combination of contusion and compression influences the early pathophysiology of SCI is important for the pre-clinical development of neuroprotective therapies that are applicable to the human condition. Disturbances in the metabolism of energy-related substrates such as lactate, pyruvate, and glucose are important aspects of secondary damage. In this study, we used a porcine model of traumatic SCI to determine the extent to which these metabolites were influenced by contusion followed by sustained compression, using the microdialysis technique. Following contusion injury, lactate and pyruvate levels near the epicenter both increased, while glucose remained quite stable. When the contusion injury was followed by sustained compression, we observed a transient rise in lactate, while pyruvate and glucose levels dropped rapidly, which may reflect decreased regional spinal cord blood flow. Furthermore, contusion with sustained compression produced a prolonged and dramatic increase in the lactate-pyruvate (L/P) ratio as a marker of tissue hypoxia, whereas after contusion injury alone, a transient and less significant elevation of the L/P ratio was observed. In this study, we demonstrate that disturbances in energy metabolism within the injured spinal cord vary greatly depending upon the biomechanical nature of the injury. Such differences are likely to be relevant to the applicability of novel therapies targeting specific aspects of the early secondary injury cascade after acute human SCI.
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http://dx.doi.org/10.1089/neu.2013.2956DOI Listing
September 2013

Characterization of a cervical spinal cord hemicontusion injury in mice using the infinite horizon impactor.

J Neurotrauma 2013 May;30(10):869-83

International Collaboration on Repair Discoveries-ICORD, Blusson Spinal Cord Center, Vancouver, British Columbia, Canada.

The majority of clinical spinal cord injuries (SCIs) are contusive and occur at the cervical level of the spinal cord. Most scientists and clinicians agree that the preclinical evaluation of novel candidate treatments should include testing in a cervical SCI contusion model. Because mice are increasingly used because of the availability of genetically engineered lines, we characterized a novel cervical hemicontusion injury in mice using the Infinite Horizon Spinal Cord Impactor (Precisions Systems & Instrumentation, Lexington, KY). In the current study, C57BL/6 mice received a hemicontusion injury of 75 kilodynes with or without dwell time in an attempt to elicit a sustained moderate-to-severe motor deficit. Hemicontusion injuries without dwell time resulted in sustained deficits of the affected forepaw, as revealed by a 3-fold decrease in usage during rearing, a ∼50% reduction in grooming scores, and retrieval of significantly fewer pellets on the Montoya staircase test. Only minor transient deficits were observed in grasping force. CatWalk analysis revealed reduced paw-print size and swing speed of the affected forelimb. Added dwell time of 15 or 30 sec significantly worsened behavioral outcome, and mice demonstrated minimal ability of grasping, paw usage, and overground locomotion. Besides worsening of behavioral deficits, added dwell time also reduced residual white and gray matter at the epicenter and rostral-caudal to the injury, including on the contralateral side of the spinal cord. Taken together, we developed and characterized a new hemicontusion SCI model in mice that produces sufficient and sustained impairments in gross and skilled forelimb function and produced primarily unilateral functional deficits.
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http://dx.doi.org/10.1089/neu.2012.2405DOI Listing
May 2013
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