Publications by authors named "Seth Tigchelaar"

26 Publications

  • Page 1 of 1

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

Tranexamic acid does not affect intraoperative blood loss or in-hospital outcomes after acetabular fracture surgery.

Eur J Orthop Surg Traumatol 2021 Apr 23. Epub 2021 Apr 23.

Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA.

Purpose: Tranexamic acid (TXA) reduces need for transfusion in total joint arthroplasty, though findings in acetabular surgery are conflicting. We compared outcomes after acetabular fracture surgery with or without perioperative intravenous (IV) TXA administration.

Methods: We performed a retrospective review of 305 patients with acetabular fractures that underwent open reduction and internal fixation (ORIF). Eighty-nine patients received TXA, and 216 did not. The primary outcome was rates of intraoperative and postoperative allogeneic blood transfusion.

Results: Baseline demographics and characteristics were similar. Time from injury to surgery and estimated blood loss were comparable. Operative time (p < 0.01) and intraoperative IV fluids (p < 0.01) were greater in the non-TXA group. The proportion of patients who received blood transfusion and mean units transfused intraoperatively and postoperatively did not differ. Mean differences in preoperative and postoperative hemoglobin and hematocrit, hospital length of stay, and perioperative complications also did not differ. In a multivariable regression model, age 60-70 years, Charlson Comorbidity Index, Injury Severity Score, and fracture patterns likely to bleed were independently associated with intraoperative transfusion. Anterior surgical approaches and intraoperative transfusion requirement were independently associated with postoperative transfusion.

Conclusion: In this study, perioperative IV TXA did not decrease blood loss, need for transfusion, or improve in-hospital outcomes of acetabular fracture surgery. Age 60-70, CCI, ISS, and fracture patterns likely to bleed were independently associated with intraoperative transfusion. Anterior surgical approach and need for intraoperative transfusion were independently associated with postoperative transfusion. Further prospective trials are warranted to confirm these findings.
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http://dx.doi.org/10.1007/s00590-021-02985-3DOI Listing
April 2021

Hypotensive Anesthesia does not reduce Transfusion Rates during and after Acetabular Fracture Surgery.

Injury 2021 Jul 2;52(7):1783-1787. Epub 2021 Apr 2.

Department of Orthopaedic Surgery, Stanford University Medical Center, Stanford, CA, USA. Electronic address:

Background: Acetabular fracture open reduction and internal fixation (ORIF) is generally associated with high intraoperative blood loss. Hypotensive anesthesia has been shown to decrease blood loss and intraoperative transfusion in total joint arthroplasty and posterior spinal fusion. In this study, we assessed the effect of reduction in intraoperative mean arterial pressures (MAPs) during acetabular fracture surgery on intraoperative blood loss and need for transfusion.

Methods: Three hundred and one patients with acetabular fractures who underwent ORIF at an academic Level 1 trauma center were retrospectively reviewed. Patients were separated based on mean intraoperative MAPs (<60 mmHg, 60-70 mmHg, >70 mmHg). Thirteen patients had mean intraoperative MAP <60 mmHg, 95 had MAP 60-70 mmHg, and 193 had MAP >70 mmHg. Rates of intraoperative and postoperative allogeneic blood transfusion were compared.

Results: Mean intraoperative MAPs were significantly different between groups (p < 0.0001). Time from injury to surgery, estimated blood loss, operative time and intraoperative IV fluids were comparable. The proportion of patients who received blood transfusion and mean units transfused intraoperatively and postoperatively were similar between groups. Mean differences in preoperative and postoperative hemoglobin and hematocrit were also similar. There was no difference in hospital length of stay or perioperative complications between the groups. Multivariate logistic regression analysis demonstrated that body mass index > 30 (p < 0.05) and anterior surgical approach (p < 0.01) were independently associated with intraoperative transfusion and an anterior surgical approach (p < 0.001) was independently associated with postoperative transfusion.

Conclusion: Decreased intraoperative MAP during acetabular fracture surgery does not reduce blood loss or need for transfusion. On the other hand, no increased end-organ ischemia was seen with hypotensive anesthesia.

Level Of Evidence: Therapeutic Level III.
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http://dx.doi.org/10.1016/j.injury.2021.03.059DOI Listing
July 2021

Indications for cement augmentation in fixation of geriatric intertrochanteric femur fractures: a systematic review of evidence.

Arch Orthop Trauma Surg 2021 Apr 7. Epub 2021 Apr 7.

Department of Orthopaedic Surgery, Stanford University Medical Center, Stanford, 450 Broadway St., Pavilion C, 4th Floor, Redwood, CA, 94063, USA.

Introduction: Achieving durable mechanical stability in geriatric intertrochanteric proximal femur fractures remains a challenge. Concomitant poor bone quality, unstable fracture patterns, and suboptimal reduction are additional risk factors for early mechanical failure. Cement augmentation of the proximal locking screw or blade is one proposed method to augment implant anchorage. The purpose of this review is to describe the biomechanical and clinical evidence for cement augmentation of geriatric intertrochanteric fractures, and to elaborate indications for cement augmentation.

Methods: The PubMed database was searched for English language studies up to January 2021. Studies that assessed effect of calcium phosphate or methylmethacrylate cement augmentation during open reduction and internal fixation of intertrochanteric fractures were included. Studies with sample size < 5, nontraumatic or periprosthetic fractures, and nonunion or revision surgery were excluded. Study selection adhered to PRISMA criteria.

Results: 801 studies were identified, of which 40 met study criteria. 9 studies assessed effect of cement augmentation on fracture displacement. All but one found that cement decreased fracture displacement. 10 studies assessed effect of cement augmentation on total load or cycles to failure. All but one demonstrated that augmented implants increased this variable. Complication rates of cement augmentation during ORIF of intertrochanteric fractures ranged from 0 to 47%, while non-augmented implants ranged from 0 to 51%. Reoperation rates ranged from 0 to 11% in the cement-augmented group and 0 to 11% in the non-augmented group. Fixation failure ranged from 0 to 11% in the cement-augmented group and 0 to 20% in the non-augmented group. Nonunion ranged from 0 to 3.6% in the cement-augmented group and 0 to 34% in the non-augmented group.

Conclusions: Calcium phosphate or PMMA-augmented CMN fixation of IT fractures increased construct stability and improved outcomes in biomechanical and early clinical studies. The findings of these studies suggest an important role for cement augmentation in patient populations at high risk of mechanical failure.
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http://dx.doi.org/10.1007/s00402-021-03872-6DOI Listing
April 2021

Medial Column Support in Pilon Fractures Using Percutaneous Intramedullary Large Fragment Fixation.

J Orthop Trauma 2021 Mar 5. Epub 2021 Mar 5.

Department of Orthopaedics and Sports Medicine, Harborview Medical Center, University of Washington, Seattle, WA325 9 Avenue, Harborview Medical Center, Seattle, WA 98104 Stanford University Department of Orthopaedic Surgery, 300 Pasteur Dr, Edwards Building, R144, Stanford, CA, 94305, USA Santa Clara Valley Medical Center Department of Orthopaedic Surgery, 751 Bascom Dr, Building Q, San Jose, CA, 95128, USA.

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http://dx.doi.org/10.1097/BOT.0000000000002073DOI Listing
March 2021

Cephalomedullary helical blade is independently associated with less collapse in intertrochanteric femur fractures than lag screws.

Eur J Orthop Surg Traumatol 2021 Feb 15. Epub 2021 Feb 15.

Department of Orthopaedic Surgery, Stanford Hospitals and Clinics, Stanford, CA, USA.

Objectives: Excessive fracture site collapse and shortening in intertrochanteric femur fractures alter hip biomechanics and patient outcomes. The purpose of the study was to compare extent of collapse in cephalomedullary nails with blades or lag screws. We hypothesized that there would be no difference in collapse between helical blades and lag screws.

Design: Retrospective cohort study.

Setting: Single U.S. Level I Trauma Center.

Patients: 171 consecutive patients treated with cephalomedullary nails with either lag screw or blade for AO/OTA 31A1-3 proximal femur fractures and minimum 3-month follow-up.

Intervention: Lag screw or helical blade in a cephalomedullary nail.

Outcome Measures: The primary outcome was fracture site collapse at 3 months.

Results: There was a significantly higher proportion of reverse-oblique and transverse intertrochanteric femur fractures (31-A3) in the lag screw group (15/42 vs 25/129). A3 patterns were associated with more collapse. There was significantly less collapse in the blade group (median 4.7 mm, inter-quartile range 2.5-7.8 mm) than the screw group (median 8.4 mmm, inter-quartile range 3.7-11.2 mm, p 0.006). Median collapse was no different between blades and screws when comparing stable and unstable patterns. However, blades were independently associated with 2.5 mm less collapse (95%CI - 4.2, - 0.72 mm, p 0.006) and lower likelihood of excessive collapse (> 10 mm at 3 months, OR 0.3, 95% CI 0.13-0.74, p 0.007), regardless of fracture pattern.

Conclusions: Helical blades are independently associated with significantly less collapse than lag screws in intertrochanteric proximal femur fractures, after adjusting for unstable fracture patterns. In fracture patterns at risk for collapse, surgeons can consider use of a helical blade due to its favorable sliding properties compared to screws.
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http://dx.doi.org/10.1007/s00590-021-02875-8DOI Listing
February 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

Gluteus Minimus Debridement During Acetabular Fracture Surgery Does Not Prevent Heterotopic Ossification - A Comparative Study.

J Orthop Trauma 2021 Jan 18. Epub 2021 Jan 18.

Investigation performed at the Department of Orthopaedic Surgery, Stanford University Medical Center, Stanford, CA.

Objectives: To compare rates of heterotopic ossification (HO) after acetabular fracture surgery, through a posterior approach, with and without gluteus minimus muscle (GMM) debridement.

Design: Retrospective comparative study.

Setting: Single academic Level I trauma center.

Patients: Ninety-four patients in the GMM preserved group and 42 patients in the GMM debrided group met inclusion criteria.

Intervention: GMM preservation or debridement during acetabular fracture surgery through a single-posterior approach.

Main Outcome Measurements: Primary outcomes were incidence and severity of HO. Reoperation for HO excision was assessed. Other risk factors for severe HO (Brooker class III-IV) were secondarily assessed using multivariable logistic regression analyses. Odds ratios (OR) with 95% confidence intervals (CI) were calculated. Significance was set at p-value ≤ 0.05.

Results: There was no difference in the incidence or severity of HO between the debrided and preserved groups. Rates of reoperation for HO excision were comparable. American Society of Anesthesiologists (ASA) physical status class (OR = 3.3), head injury (OR = 4.6), and abdominal injury (OR = 4.5) were associated with severe HO.

Conclusion: GMM debridement was not associated with a decreased incidence of HO after acetabular fracture surgery. ASA class is a novel risk factor associated with severe HO formation.

Level Of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.1097/BOT.0000000000002061DOI Listing
January 2021

Management of the posterior wall fracture in associated both column fractures of the acetabulum.

Eur J Orthop Surg Traumatol 2021 Aug 1;31(6):1047-1054. Epub 2021 Jan 1.

Department of Orthopaedic Surgery, Stanford University, 450 Broadway Street, Pavilion C, 4th Floor, Redwood City, CA, 94063-6342, USA.

Purpose: The primary aim of this study was to compare clinical outcomes in patients with associated both column (ABC) acetabular fractures with fracture of the posterior wall (PW), in which the PW underwent reduction and fragment-specific fixation versus those that were treated with column fixation alone. Secondary aims were to assess PW fracture incidence and morphology, as well as to compare radiographic outcomes including fracture healing and interval displacement of the PW in those that did and did not undergo fragment-specific fixation of the PW.

Methods: This was a retrospective series of ABC acetabular fractures treated at a single Level I trauma center. Separate fractures of the PW were identified, and associated features were assessed. Associated both column fractures that underwent reduction and fragment-specific fixation of the PW where then compared to ABC fractures with PW involvement that underwent column reconstruction alone. Radiographic and clinical outcomes were compared.

Results: Fractures of the PW occurred in 55.7% of ABC fractures and were associated with central displacement of the femoral head. The majority of PW fractures were large and involved the acetabular roof. All PW fractures healed without displacement by 3 months, regardless of whether or not reduction and stabilization was performed. Mid-term outcomes at 1-year were similar regardless of whether or not the PW was reduced and stabilized, with regards to Tönnis grade, Merle d'Aubigné-Postel score, and conversion to total hip arthroplasty.

Conclusion: Reduction and fragment-specific fixation of the PW component of ABC acetabular fractures did not improve outcomes in this small comparative study. Posterior wall fractures associated with ABC patterns are frequently large-sized fragments that involve the acetabular roof and are rendered stable after reconstruction of the columns.
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http://dx.doi.org/10.1007/s00590-020-02850-9DOI Listing
August 2021

Lateral Distractor Use During Internal Fixation of Tibial Plateau Fractures Has a Minimal Risk of Iatrogenic Peroneal Nerve Palsy.

J Orthop Trauma 2021 02;35(2):e51-e55

Department of Orthopaedic Surgery, Stanford University Medical Center, Stanford, CA.

Objectives: To determine the incidence of iatrogenic peroneal nerve palsy after application of an intraoperative lateral distractor during open reduction and internal fixation of tibial plateau fractures.

Design: Retrospective review.

Setting: Single academic Level I trauma center.

Patients: One hundred forty-seven patients met criteria and were included in the study.

Intervention: Patients with unicondylar and bicondylar tibial plateau fractures underwent open reduction and internal fixation and received application of an intraoperative lateral distractor to aid in visualization and reduction of the impacted lateral plateau.

Main Outcome Measurements: Incidence of iatrogenic peroneal nerve palsy.

Results: There was a 2.0% incidence of iatrogenic peroneal nerve symptoms (3 of 147 patients), most of which were incomplete sensory deficits. There was no association with staged external fixation, regional anesthesia, or tourniquet use.

Conclusion: Use of an intraoperative lateral distractor is safe and has a low incidence of iatrogenic peroneal nerve palsy if applied carefully.

Level Of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.1097/BOT.0000000000001875DOI Listing
February 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

Trochanteric fixation nail advanced with helical blade and cement augmentation: early experience with a retrospective cohort.

Eur J Orthop Surg Traumatol 2021 Feb 17;31(2):259-264. Epub 2020 Aug 17.

Department of Orthopaedic Surgery, Stanford University School of Medicine, 300 Pasteur Drive Room R144, Stanford, CA, 94305, USA.

Intra-articular screw cut-out is a potential complication of intertrochanteric femur fracture fixation with a cephalomedullary nail. Cement augmentation of fixation in the proximal segment offers the prospect of increased stability and fewer complications, but clinical experience with non-resorbable cement is limited. To determine the handling properties and efficacy of this new technique, we performed a retrospective propensity-matched cohort of forty-four geriatric intertrochanteric femur fractures treated with a cephalomedullary nail with (n = 11) or without (n = 33) augmentation with non-resorbable cement injected into the proximal segment. In the patients treated with cement augmentation, at minimum 3-month follow-up, there were no instances of intra-articular cut-out, and no increase in re-operation compared to conventional fixation. Cement augmentation appears to be safe and effective in geriatric intertrochanteric femur fractures to mitigate risk of cut-out.
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http://dx.doi.org/10.1007/s00590-020-02762-8DOI Listing
February 2021

Trochanteric osteotomy for acetabular fracture fixation: a case series and literature review.

Eur J Orthop Surg Traumatol 2021 Jan 3;31(1):161-165. Epub 2020 Aug 3.

Department of Orthopaedic Surgery, Stanford University Medical Center, 450 Broadway Street, Pavilion C, 4th Floor, Redwood City, CA, 94063-6342, USA.

Purpose: This study examined osteotomy union and heterotopic ossification (HO) after performing digastric trochanteric osteotomies during open reduction and internal fixation (ORIF) of acetabular and combined femoral head fractures. Femoral head osteonecrosis and trochanteric screw removal were secondarily assessed.

Methods: Twenty-six patients treated at a Level I trauma center, from years 2003 to 2019, who received a digastric trochanteric osteotomy during acetabular and combined femoral head fracture ORIF through a posterior surgical approach were retrospectively identified. Osteotomies were fixed with two 3.5 mm cortical lag screws. Rates of osteotomy union, HO, femoral head osteonecrosis, and trochanteric screw removal were determined.

Results: All osteotomies went onto union without displacement or failure of fixation. Only three (12%) patients developed severe HO (modified-Brooker class III-IV). There were no instances of femoral head osteonecrosis and only one (7%) patient required trochanteric screw removal.

Conclusions: The digastric trochanteric osteotomy heals reliably with low rates of severe HO, femoral head osteonecrosis, and screw removal for soft-tissue irritation. A review of the literature is presented and found comparable findings.
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http://dx.doi.org/10.1007/s00590-020-02753-9DOI Listing
January 2021

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

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

Integrated systems analysis reveals conserved gene networks underlying response to spinal cord injury.

Elife 2018 10 2;7. Epub 2018 Oct 2.

Centre for High-Throughput Biology, University of British Columbia, Vancouver, Canada.

Spinal cord injury (SCI) is a devastating neurological condition for which there are currently no effective treatment options to restore function. A major obstacle to the development of new therapies is our fragmentary understanding of the coordinated pathophysiological processes triggered by damage to the human spinal cord. Here, we describe a systems biology approach to integrate decades of small-scale experiments with unbiased, genome-wide gene expression from the human spinal cord, revealing a gene regulatory network signature of the pathophysiological response to SCI. Our integrative analyses converge on an evolutionarily conserved gene subnetwork enriched for genes associated with the response to SCI by small-scale experiments, and whose expression is upregulated in a severity-dependent manner following injury and downregulated in functional recovery. We validate the severity-dependent upregulation of this subnetwork in rodents in primary transcriptomic and proteomic studies. Our analysis provides systems-level view of the coordinated molecular processes activated in response to SCI.
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http://dx.doi.org/10.7554/eLife.39188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173583PMC
October 2018

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

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

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

A novel porcine model of traumatic thoracic spinal cord injury.

J Neurotrauma 2013 Feb 14;30(3):142-59. Epub 2013 Jan 14.

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

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.
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http://dx.doi.org/10.1089/neu.2012.2386DOI Listing
February 2013

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

J Vis Exp 2012 Jul 24(65). Epub 2012 Jul 24.

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

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.
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http://dx.doi.org/10.3791/3313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3479980PMC
July 2012

Lack of neuroprotective effects of simvastatin and minocycline in a model of cervical spinal cord injury.

Exp Neurol 2010 Sep 28;225(1):219-30. Epub 2010 Jun 28.

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

Minocycline, a commonly prescribed tetracycline antibiotic, has shown promise as a potential therapeutic agent in animal models of numerous neurologic disorders such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Huntington's disease, stroke, and spinal cord injury (SCI). Simvastatin is one of many hydroxymethylglutaryl-coenzyme-A reductase inhibitors prescribed to lower cholesterol. These drugs are also known to reduce inflammation and oxidative stress, improve endothelial function, and modulate the immune system in stroke, traumatic brain injury, and SCI. As both drugs have translational potential, we evaluated their neuroprotective properties here in a clinically relevant model of contusive cervical spinal cord injury. Sprague-Dawley rats underwent a unilateral cervical contusion SCI at C5 and were randomized to receive: 1. Minocycline 90 mg/kg x 3 days, 2. Simvastatin 20 mg/kg x 7 days, 3. Simvastatin 20 mg/kg x 7 days then 5mg/kg x 35 days, or 4. Saline (Control). Behavioral recovery was assessed over 6 weeks using the horizontal ladder test, cylinder rearing test, modified Montoya staircase test and grooming test. Forepaw sensitivity was also assessed using the electronic von Frey Aesthesiometer. The corticospinal and rubrospinal tracts were traced and the spinal cords were harvested 7 weeks after injury. The extent of gray matter and white matter sparing and corticospinal and rubrospinal tract sprouting were evaluated in cross sections of the spinal cord. In the end, neither minocycline nor simvastatin treatment was associated with improved performance on the behavioral tests, as compared to saline controls. Performance on the horizontal ladder test, cylinder rearing test, and von Frey sensory test were similar among all groups. Animals treated for 42 days with simvastatin scored significantly higher in the grooming score compared to other groups, but retrieved significantly fewer pellets on the modified Montoya staircase test than control and minocycline treated animals. Histologically, there were no significant differences in white and gray matter sparing and in the extent of corticospinal and rubrospinal sprouting between the four groups. In conclusion, both minocycline and simvastatin failed to improve functional and histological recovery in our model of contusive cervical spinal cord injury.
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http://dx.doi.org/10.1016/j.expneurol.2010.06.018DOI Listing
September 2010
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