Demonstrating efficacy in preclinical studies of cellular therapies for spinal cord injury - how much is enough?

Cellular therapies represent a novel treatment approach for spinal cord injury (SCI), with many different cellular substrates showing promise in preclinical animal models of SCI. Considerable interest therefore exists to translate such cellular interventions into human clinical trials. Balanced against the urgency for clinical translation is the desire to establish the robustness of a cellular therapy's efficacy in preclinical studies, thereby optimizing its chances of succeeding in human trials.

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).

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.

The validity of administrative data to classify patients with spinal column and cord injuries.

International Classification of Diseases (ICD) codes are used to document patient morbidity in administrative databases. Although administrative data are used for research purposes, the validity of the data to accurately describe clinical diagnostic information is uncertain. We compared the clinical diagnoses for spinal cord and column injuries from a longitudinal patient registry, the Rick Hansen Spinal Cord Injury Registry (RHSCIR), to the ICD-10 spinal injury codes from the Discharge Abstract Database (DAD) at one institution.

Expectations of benefit and tolerance to risk of individuals with spinal cord injury regarding potential participation in clinical trials.

We conducted a survey of individuals living with spinal cord injury (SCI) to determine their receptivity to participating in clinical trials of drug therapies or stem cell therapies, their anticipation of therapeutic benefits, and their tolerance to risk. A 46-item questionnaire was administered to individuals with cervical or thoracic SCI identified through a provincial database. The average age was 42 years and the individuals were, on average, 5.

Feasibility of patient recruitment into clinical trials of experimental treatments for acute spinal cord injury.

Clinical trials of experimental neuroprotective and neuroregenerative therapies for acute spinal cord injury (SCI) typically require large numbers of patients to be enrolled. An important factor in designing such trials is the number of patients that can be realistically recruited at a given institution. The total number of patients with acute SCI treated at a neurotrauma centre is typically considered when such a site becomes a recruiting centre for a clinical trial.

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.

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.

Decision-making in stem cell trials for spinal cord injury: the role of networks and peers.

Aims: The purpose of this study was to characterize the self-perceived role of professionals and personal caregivers in decision-making about participation in stem cell clinical trials by individuals in early post-spinal cord injury time-points.

Materials & Methods: Data were obtained from focus groups and semi-structured individual interviews from two networks: healthcare professionals (e.g.

Opinions on the preclinical evaluation of novel therapies for spinal cord injury: a comparison between researchers and spinal cord-injured individuals.

We previously conducted a survey to gather the opinions and perspectives of scientific and clinical researchers on what levels of preclinical evidence were needed to justify translating a promising neuroprotective or neuroregenerative therapy in spinal cord injury (SCI) into a human clinical trial (Kwon et al., 2010 ). Here we conducted an analogous survey of individuals living with SCI in which we gathered their expectations for the levels of preclinical evidence achieved by researchers in substantiating the neuroprotective and neuroregenerative therapies being offered to them in clinical trials.

Intra-operative cone-beam CT (O-arm) and stereotactic navigation in acute spinal trauma surgery.

The purpose of this ambispective cohort study is to describe the emerging role of intra-operative cone-beam CT (O-arm®, Medtronic, Minneapolis, MN, USA), frequently coupled with stereotactic navigation (StealthStation®, Medtronic), in the surgical management of acute spinal trauma. All patients with acute spinal trauma between May 2009 and May 2011 who were treated with the use of the O-arm were identified from a prospectively collected spine database and retrospectively analyzed to characterize indications and outcomes. Over the two-year period, the O-arm was used in 183 spinal operations; 27 of these (15%) involved acute spinal trauma.

The spine-injured patient: initial assessment and emergency treatment.

Failure to recognize spinal column or spinal cord injuries, or improper treatment of them, can have catastrophic and often irreversible neurologic consequences. Although the initial assessment is often shared with emergency care personnel, an orthopaedic surgeon's perspective can elevate the priority of spinal care to the level that is warranted. An accurate early appraisal, including complete neurologic assessment, is critical.

Association between degenerative spondylolisthesis and spinous process fracture after interspinous process spacer surgery.

Background Context: Spinous process fracture is a recognized complication associated with interspinous process spacer (IPS) surgery. Although occasionally identified by plain radiographs, computed tomography (CT) appears to identify a higher rate of such fractures. Although osteoporotic insufficiency fracture is considered a contraindication for IPS surgery, a formal risk factor analysis for this complication has not previously been reported.

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.

Vascular disruption and the role of angiogenic proteins after spinal cord injury.

Spinal cord injuries (SCI) can result in devastating paralysis, for which there is currently no robustly efficacious neuroprotective/neuroregenerative treatment. When the spinal cord is subjected to a traumatic injury, the local vasculature is disrupted and the blood-spinal cord barrier is compromised. Subsequent inflammation and ischemia may then contribute to further secondary damage, exacerbating neurological deficits.

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

Study Design: Quantitative in vivo ultrasound imaging study of spinal cord and dura morphology after acute experimental spinal cord injury (SCI) and decompression in a pig model.

Objective: To study the morphological changes of the spinal cord and dura immediately after surgical decompression for acute SCI.

Summary Of Background Data: Surgical decompression for traumatic SCI is currently a topic of debate.

Postoperative infection treatment score for the spine (PITSS): construction and validation of a predictive model to define need for single versus multiple irrigation and debridement for spinal surgical site infection.

Background Context: There is very little evidence to guide treatment of patients with spinal surgical site infection (SSI) who require irrigation and debridement (I&D) in deciding need for single or multiple I&Ds or more complex wound management such as vacuum-assisted closure dressing or soft-tissue flaps.

Purpose: The purpose of this study was to build a predictive model that stratifies patients with spinal SSI, allowing us to determine which patients will need single versus multiple I&D. The model will be validated and will serve as evidence to support a scoring system to guide treatment.

Mechanical indicators of injury severity are decreased with increased thecal sac dimension in a bench-top model of contusion type spinal cord injury.

The cerebrospinal fluid (CSF) is thought to protect the spinal cord from physiologic loading; however, it is unclear whether this protective role extends to traumatic events in which bone fragments enter the canal at high velocity. A synthetic model of the spinal neural anatomy, with mechanical properties similar to native tissues, was constructed to determine if the thickness of the CSF layer (0, 12.8, 19.

The epidemiology of traumatic spinal cord injury in British Columbia, Canada.

Study Design: Retrospective observational study utilizing prospectively collected population-based data.

Objective: To describe the epidemiology and demographics of all patients with traumatic spinal cord injury (TSCI) treated at a single institution, which represents the sole referral center and specialized SCI unit for a population of 4 million people.

Summary Of Background Data: Although many studies report on the epidemiology of TSCI, studies in which patients are prospectively characterized in the acute setting with precise recording of their baseline neurological impairment are uncommon.

Morbidity and mortality of major adult spinal surgery. A prospective cohort analysis of 942 consecutive patients.

Background Context: To date, most reports on the incidence of adverse events (AEs) in spine surgery have been retrospective and dependent on data abstraction from hospital-based administrative databases. To our knowledge, there have been no previous rigorously performed prospective analysis of all AEs occurring in the entire population of patients presenting to an academic quaternary referral center.

Purpose: To determine the mortality and true incidence and severity of morbidity (major and minor, medical and surgical) in adults undergoing complex spinal surgery, both trauma and elective, in a quaternary referral center.

Primary pyogenic infection of the spine in intravenous drug users: a prospective observational study.

Study Design: A prospective comparative analysis of surgically-treated nontuberculous primary pyogenic infection of the spine (PPIS).

Objective: To evaluate and compare the demographics, presentation, treatment and outcomes of surgically-treated PPIS between intravenous drug users (IVDU) and non-IVDU patients.

Summary Of Background Data: This is the first prospective cohort comparative analysis of the clinical outcomes of surgically-treated PPIS between IVDU and non-IVDU populations.

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.

A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury.

Multiple lines of evidence have validated the Rho pathway as important in controlling the neuronal response to growth inhibitory proteins after central nervous system (CNS) injury. A drug called BA-210 (trademarked as Cethrin(®)) blocks activation of Rho and has shown promise in pre-clinical animal studies in being used to treat spinal cord injury (SCI). This is a report of a Phase I/IIa clinical study designed to test the safety and tolerability of the drug, and the neurological status of patients following the administration of a single dose of BA-210 applied during surgery following acute SCI.

Occult spinous process fractures associated with interspinous process spacers.

Study Design: Prospective observational study.

Objective: To provide a more accurate estimate of the rate of acute spinous process fractures associated with IPS surgery.

Summary Of Background Data: Biomechanical cadaveric studies have suggested adequate spinous process strength to support placement of interspinous process spacers (IPS).

Inflammatory and structural biomarkers in acute traumatic spinal cord injury.

The paralysis of an acute spinal cord injury (SCI) remains a catastrophic condition for which there are currently no effective treatments. While the diagnosis of acute traumatic SCI is typically quite easy to make, distinguishing the exact degree of severity and prognosticating the extent of neurologic recovery are challenging. Functional neurologic measures are currently used to stratify injury severity and predict neurologic outcome.