Rapidly developed heterotopic ossification: a rare complication after trauma.

Heterotopic ossification (HO) is a condition where aberrant bone grows in tissues. This case study presents a rare complication of trauma and laparotomies, where the rapid and extensive occurrence of HO has delayed abdominal incision closure resulting in multiple surgeries and prolonged recovery. A 44-year-old man was retrieved after a truck accident resulting in multi-organ injuries. He required damage control trauma laparotomy followed by several relooks and multiple orthopaedic procedures. Despite several attempts, approximation of the laparostomy wound was not possible due to abdominal rigidity. Computed tomography scans done 20 days after injury demonstrated advanced HO over the wound edge. Early development of HO may explain why the abdominal incision was difficult to close and highlights the importance of being aware of HO as an early complication after trauma and midline laparotomy.

Comparing clinical outcomes between rotator cuff repairs, SLAP repairs, and combined repairs.

BACKGROUND: Superior labrum lesion from anterior to posterior (SLAP) often presents together with other shoulder pathologies such as rotator cuff tear (RCT), but it is uncertain if repairing both SLAP and RCT has superior clinical outcomes over isolated repairs of SLAP and RCT. MATERIALS AND METHODS: This was a retrospective cohort study with prospectively collected data, reviewing 157 patients who underwent arthroscopic repair of either RCT, SLAP (type II lesion), or both. Before surgery and after 6 weeks, 12 weeks, and 24 weeks, shoulder objective range of motion and strength were measured, patient-reported function and pain was assessed by the modified L'Insalata questionnaire with a Likert scale, and complications after each repair were examined. RESULTS: At 24 weeks after surgery, the combined group (n = 22) and SLAP group (n = 47) had significantly higher forward flexion (165° ± 4° and 167° ± 4° vs. 154° ± 3°, P = .01 and P = .01), external rotation strength (82 ± 6 N, 81 ± 6 N vs. 61 ± 3 N, P = .01 and P = .01), and abduction strength (94 ± 14 N, 78 ± 8 N vs. 53 ± 3 N, P = .001 and P = .02) compared with the rotator cuff tear repair (RCR) group (n = 88). The combined group also had stronger internal rotation than the RCR group (107 ± 12 N vs. 72 ± 4 N, P = .02). Function and pain improved from "severe-moderate" to "moderate-mild" in all groups after surgery. CONCLUSION: Repairing RCT and SLAP tears together results in significant clinical benefits compared to repairing just RCT and analogous results against SLAP-only repair.

Cytotoxicity and biomechanics of suture anchors used in labral repairs.

BACKGROUND: Biodegradable suture anchors are associated with higher redislocation rates. This study examined whether the biocompatibility and/or biomechanical properties of suture anchors contribute to the increase in complications. METHODS: Human glenohumeral capsule cells were cultured with 4 types of suture anchors, Opus LabraFix (titanium alloy; ArthroCare, Austin, TX, USA), PushLock (poly-ether-ether-ketone; Arthrex, Naples, FL, USA), BioKnotless (poly-l-lactic acid; DePuy Mitek, Warsaw, IN, USA), and Suretac II (polyglycolic acid; Smith & Nephew, London, UK), to measure cell viability and pH. Four groups of 6 ovine shoulders were used to repair the labrum, which was completely detached from the glenoid rim anteroinferiorly and reattached with 2 suture anchors and subject to failure load testing. RESULTS: In cell culture, BioKnotless at 48 and 72 hours (85.2% ± 2.1% and 84.5% ± 3.6%) and Suretac II groups (33.9% ± 3.1% and 42.8% ± 6.4%) had fewer viable cells compared with control (P = .048). The pH of Suretac II was lower than control (7.51 to 7.65) at 24 hours (7.31 ± 0.08, P = .049), 48 hours (7.25 ± 0.02, P = .046), and 72 hours (7.29 ± 0.04, P = .04). During mechanical testing, 83% of repairs failed by the capsule tearing. Among the anchors, the BioKnotless repair group had a significantly lower failure load (37 ± 5 N) compared with the PushLock (61 ± 7 N), Opus (60 ± 6 N), and Suretac II (57 ± 7 N) groups (P = .038). CONCLUSION: BioKnotless and Suretac II anchors are cytotoxic. The BioKnotless biodegradable anchor has significantly lower failure load. Absorbable suture anchors may cause higher redislocation of arthroscopic Bankart repair.

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

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.

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

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; PaPO2), 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, PaPO2 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.

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

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.

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

A porcine model of spinal cord injury (SCI) was used to evaluate the neuroprotective effects of magnesium chloride (MgCl2) 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 (MgSO4), 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 MgSO4 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 MgSO4 treatment. Histological analysis revealed no significant increase in gray or white matter sparing with AC105 or MgSO4 treatment. Finally, AC105 did not result in higher Mg2+ levels in CSF than with the use of standard MgSO4. 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.

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

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.

Nonlinear viscoelastic characterization of the porcine spinal cord.

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.

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

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.

Cerebrospinal fluid pressures resulting from experimental traumatic spinal cord injuries in a pig model.

Despite considerable effort over the last four decades, research has failed to translate into consistently effective treatment options for spinal cord injury (SCI). This is partly attributed to differences between the injury response of humans and rodent models. Some of this difference could be because the cerebrospinal fluid (CSF) layer of the human spine is relatively large, while that of the rodents is extremely thin. We sought to characterize the fluid impulse induced in the CSF by experimental SCIs of moderate and high human-like severity, and to compare this with previous studies in which fluid impulse has been associated with neural tissue injury. We used a new in vivo pig model (n = 6 per injury group, mean age 124.5 days, 20.9 kg) incorporating four miniature pressure transducers that were implanted in pairs in the subarachnoid space, cranial, and caudal to the injury at 30 mm and 100 mm. Tissue sparing was assessed with Eriochrome Cyanine and Neutral Red staining. The median peak pressures near the injury were 522.5 and 868.8 mmHg (range 96.7-1430.0) and far from the injury were 7.6 and 36.3 mmHg (range 3.8-83.7), for the moderate and high injury severities, respectively. Pressure impulse (mmHg.ms), apparent wave speed, and apparent attenuation factor were also evaluated. The data indicates that the fluid pressure wave may be sufficient to affect the severity and extent of primary tissue damage close to the injury site. However, the CSF pressure was close to normal physiologic values at 100 mm from the injury. The high injury severity animals had less tissue sparing than the moderate injury severity animals; this difference was statistically significant only within 1.6 mm of the epicenter. These results indicate that future research seeking to elucidate the mechanical origins of primary tissue damage in SCI should consider the effects of CSF. This pig model provides advantages for basic and preclinical SCI research due to its similarities to human scale, including the existence of a human-like CSF fluid layer.

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

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.

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

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.

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.

A contusive model of unilateral cervical spinal cord injury using the infinite horizon impactor.

While the majority of human spinal cord injuries occur in the cervical spinal cord, the vast majority of laboratory research employs animal models of spinal cord injury (SCI) in which the thoracic spinal cord is injured. Additionally, because most human cord injuries occur as the result of blunt, non-penetrating trauma (e.g. motor vehicle accident, sporting injury) where the spinal cord is violently struck by displaced bone or soft tissues, the majority of SCI researchers are of the opinion that the most clinically relevant injury models are those in which the spinal cord is rapidly contused.(1) Therefore, an important step in the preclinical evaluation of novel treatments on their way to human translation is an assessment of their efficacy in a model of contusion SCI within the cervical spinal cord. Here, we describe the technical aspects and resultant anatomical and behavioral outcomes of an unilateral contusive model of cervical SCI that employs the Infinite Horizon spinal cord injury impactor. Sprague Dawley rats underwent a left-sided unilateral laminectomy at C5. To optimize the reproducibility of the biomechanical, functional, and histological outcomes of the injury model, we contused the spinal cords using an impact force of 150 kdyn, an impact trajectory of 22.5° (animals rotated at 22.5°), and an impact location off of midline of 1.4 mm. Functional recovery was assessed using the cylinder rearing test, horizontal ladder test, grooming test and modified Montoya's staircase test for up to 6 weeks, after which the spinal cords were evaluated histologically for white and grey matter sparing. The injury model presented here imparts consistent and reproducible biomechanical forces to the spinal cord, an important feature of any experimental SCI model. This results in discrete histological damage to the lateral half of the spinal cord which is largely contained to the ipsilateral side of injury. The injury is well tolerated by the animals, but does result in functional deficits of the forelimb that are significant and sustained in the weeks following injury. The cervical unilateral injury model presented here may be a resource to researchers who wish to evaluate potentially promising therapies prior to human translation.

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.

Development of a large-animal model to measure dynamic cerebrospinal fluid pressure during spinal cord injury: Laboratory investigation.

OBJECT: Spinal cord injury (SCI) often results in considerable permanent neurological impairment, and unfortunately, the successful translation of effective treatments from laboratory models to human patients is lacking. This may be partially attributed to differences in anatomy, physiology, and scale between humans and rodent models. One potentially important difference between the rodent and human spinal cord is the presence of a significant CSF volume within the intrathecal space around the human cord. While the CSF may "cushion" the spinal cord, pressure waves within the CSF at the time of injury may contribute to the extent and severity of the primary injury. The objective of this study was to develop a model of contusion SCI in a miniature pig and establish the feasibility of measuring spinal CSF pressure during injury. METHODS: A custom weight-drop device was used to apply thoracic contusion SCI to 17 Yucatan miniature pigs. Impact load and velocity were measured. Using fiber optic pressure transducers implanted in the thecal sac, CSF pressures resulting from 2 injury severities (caused by 50-g and 100-g weights released from a 50-cm height) were measured. RESULTS: The median peak impact loads were 54 N and 132 N for the 50-g and 100-g injuries, respectively. At a nominal 100 mm from the injury epicenter, the authors observed a small negative pressure peak (median -4.6 mm Hg [cranial] and -5.8 mm Hg [caudal] for 50 g; -27.6 mm Hg [cranial] and -27.2 mm Hg [caudal] for 100 g) followed by a larger positive pressure peak (median 110.5 mm Hg [cranial] and 77.1 mm Hg [caudal] for 50 g; 88.4 mm Hg [cranial] and 67.2 mm Hg [caudal] for 100 g) relative to the preinjury pressure. There were no significant differences in peak pressure between the 2 injury severities or the caudal and cranial transducer locations. CONCLUSIONS: A new model of contusion SCI was developed to measure spinal CSF pressures during the SCI event. The results suggest that the Yucatan miniature pig is an appropriate model for studying CSF, spinal cord, and dura interactions during injury. With further development and characterization it may be an appropriate in vivo large-animal model of SCI to answer questions regarding pathological changes, therapeutic safety, or treatment efficacy, particularly where humanlike dimensions and physiology are important.

Biomarkers for severity of spinal cord injury in the cerebrospinal fluid of rats.

One of the major challenges in management of spinal cord injury (SCI) is that the assessment of injury severity is often imprecise. Identification of reliable, easily quantifiable biomarkers that delineate the severity of the initial injury and that have prognostic value for the degree of functional recovery would significantly aid the clinician in the choice of potential treatments. To find such biomarkers we performed quantitative liquid chromatography-mass spectrometry (LC-MS/MS) analyses of cerebrospinal fluid (CSF) collected from rats 24 h after either a moderate or severe SCI. We identified a panel of 42 putative biomarkers of SCI, 10 of which represent potential biomarkers of SCI severity. Three of the candidate biomarkers, Ywhaz, Itih4, and Gpx3 were also validated by Western blot in a biological replicate of the injury. The putative biomarkers identified in this study may potentially be a valuable tool in the assessment of the extent of spinal cord damage.

Intermittent fasting improves functional recovery after rat thoracic contusion spinal cord injury.

Spinal cord injury (SCI) often results in a loss of motor and sensory function. Currently there are no validated effective clinical treatments. Previously we found in rats that dietary restriction, in the form of every-other-day fasting (EODF), started prior to (pre-EODF), or after (post-EODF) an incomplete cervical SCI was neuroprotective, increased plasticity, and promoted motor recovery. Here we examined if EODF initiated prior to, or after, a T10 thoracic contusion injury would similarly lead to enhanced functional recovery compared to ad libitum feeding. Additionally, we tested if a group fed every day (pair-fed), but with the same degree of restriction as the EODF animals (∼25% calorie restricted), would also promote functional recovery, to examine if EODF's effect is due to overall calorie restriction, or is specific to alternating sequences of 24-h fasts and ad libitum eating periods. Behaviorally, both pre- and post-EODF groups exhibited better functional recovery in the regularity indexed BBB ambulatory assessment, along with several parameters of their walking pattern measured with the CatWalk device, compared to both the ad-libitium-fed group as well as the pair-fed group. Several histological parameters (intensity and symmetry of serotonin immunostaining caudal to the injury and gray matter sparing) correlated with functional outcome; however, no group differences were observed. Thus besides the beneficial effects of EODF after a partial cervical SCI, we now report that alternating periods of fasting (but not pair-fed) also promotes improved hindlimb locomotion after thoracic spinal cord contusion, demonstrating its robust effect in two different injury models.

Magnesium in a polyethylene glycol formulation provides neuroprotection after unilateral cervical spinal cord injury.

STUDY DESIGN: Experimental animal study. OBJECTIVE: To investigate the neuroprotective efficacy of this magnesium in polyethylene glycol (PEG) formulation in a contusive model of cervical spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA: Intravenously administered magnesium has been extensively investigated as a neuroprotective agent in animal models of SCI, stroke, and traumatic brain injuries, and has been evaluated in large scale clinical trials for the latter 2 indications. We have developed a novel formulation of magnesium chloride (MgCl2) within PEG, and have previously demonstrated the neuroprotective benefit of this formulation in animal models of thoracic SCI. METHODS: Twenty-two Sprague Dawley rats underwent a unilateral cervical hemicontusion at C4-C5 and were randomized 2 hours later to either the MgCl2 in PEG formulation, or normal saline. Each treatment was administered in 5 intravenous infusions spaced 6 hours apart. Behavioral recovery was assessed over 6 weeks, after which the cord was analyzed to measure the extent of gray matter and white matter sparing through the injury site. RESULTS: In the horizontal ladder test, the percentage of forelimb errors made by the animals treated with MgCl2 in PEG formulation was significantly lower than the saline-treated controls. Histologic analysis also revealed a significantly higher cumulative white matter sparing through the injury site in the MgCl2 in PEG group. CONCLUSION: MgCl2 in a PEG formulation reduced secondary damage and improved behavioral recovery when administered 2 hours after a unilateral cervical hemicontusion injury. These findings are consistent with the neurologic benefit observed when administering this magnesium formulation in contusive and compressive models of thoracic SCI. Demonstrating the robustness of this neuroprotective effect in multiple injury models (and in the cervical injury model in particular) is important when considering the applicability of such a therapy for human SCIs.