Spinal Cord Injury Models
The summer of 2021 is the summer of the Olympic and Paralympic games in Tokyo. It has been amazing to see how world records are broken time after time as we see athletes push themselves beyond what we considered to be the limitations of a healthy human body. It may be even more admirable to see what Paralympic athletes accomplish, some of whom have significant spinal injuries. What most of us don’t know about this type of injury is that people with spinal cord injury have much more to cope with than poorly or non-functional arms and/or legs. As we have learned from the research of Dr. West, their cardiovascular system is significantly affected as well. Making the accomplishments of Paralympic athletes with SCI even more impressive.
During the last years, there has been an increase in interest and publications regarding spinal cord injury (SCI) models. The topic has been gaining more and more attention, as researchers have not only been developing these models and the subject has been gaining momentum, but the scientific community has also learned that certain levels of damage may not be unrepairable. The human body may be able to do much more self-repair than we considered possible a decade ago, much like the world records that keep getting broken. We just need to give the body what it needs.
As we are learning something new every day regarding anatomical and pathophysiological mechanisms involved in SCI, the Paralympic summer of 2021 seemed to be a perfect time to discuss the different models of SCI and their applicability in biomedical research. We hope that this will entice our readers into learning more about this exciting and complex research field.
The development of any animal model must aim for a high translational value, taking in consideration the nuances of the pathology, model-species variations and outcomes. When studying SCI models, one must contemplate how the injury source (ischemia/reperfusion, trauma, transection, and others) and location (cervical, thoracic, etc.) can be best reproduced in a model, while also pondering for animal-specific variations in outcomes. A good example can be seen in rodent contusion models; in rats, contusion injuries lead to cavities and cyst formation while mice develop dense scar tissue (more reflective of laceration and heavy compression injuries in the clinic). Another interesting difference between experimental and clinical manifestation pertains the contusion and compression injuries’ anatomical location.
SCI models are not limited to rodents or small animal models, having a significant number of studies applying other large animal models such as dogs, rabbits, pigs, and nonhuman primates.
Although bringing a better understanding of the pathophysiology and proposing novelty therapeutics, the volume of data obtained in animal studies has not yielded the desired and expected translational outcome. In favor of minimizing discrepancies between animal studies and clinical trials, SCI models should be performed following several standards for reproducibility and endpoints classification/scoring criteria. Here are some of many methods and classifications used to safeguard reproducibility and endpoint measurements in SCI models.
Trauma Induced SCI Models
In patients, impact and compression are the most common causes of SCI. Corresponding experimental models mostly use a weight drop to affect the animal dorsal spinal cord. In order to avoid different degrees of compression depending on the materials and apparatus, the methodology should account for calibrated weight, drop height (impact velocity, impulse increased, impact energy) and the lesion depth and outcomes. Although pneumatic impact devices exist and can deliver specific impact levels and therefore different injury degrees, these devices are cost prohibitive in many labs. Thus, the high importance to standardize lesion induction methodology in cost-effective approaches using any variation of contusion impactors. Compression is also used in trauma-induced models, and the technique mainly based on diverse target spinal cord thickness over specific time windows with good correlation to histopathological injury and behavioral outcomes scores. In tractive SCI, the injury is induced by a spinal retractor implanted through a laminectomy and produce a cost-effective and reliable model. Surgical spinal cord transection can be included in the trauma-induced injury category or as standalone class. It is a surgical procedure that can be used at different thoracic vertebrae levels but is categorized by low survival rates and somewhat limited to more acute or subacute models.
Ischemia-reperfusion SCI models
In the clinic, aortic (thoracic or thoracoabdominal) aneurysm repair surgery has unfortunate and common outcomes related to ischemia and/or reperfusion. These outcomes can result in delayed neuronal death, neurological dysfunction, and immediate or delayed paraplegia. Most animal models used to evaluate this specific injury source use transient aortic occlusion (or cross-clamping) and have uncovered pathophysiological mechanisms and neuroprotective strategies. These include systemic hypothermia and cerebrospinal fluid drainage, ischemic preconditioning for better ischemic tolerance, and molecular pathways involved in angiogenesis, neuronal apoptosis, and regeneration of medullary sheath.
The review article “Animal models of spinal cord injury: a systematic review” (M Sharif-Alhoseini et al. Spinal Cord 55, 714–721. 2017) gives a detailed review of SCI animal models per aims and injury outcomes tests used in research. Most of the catalogued studies used at least 2 methods in distinct categories.
In summary the outcomes can be largely grouped according to the following methodology:
- Histology (staining and immunostaining methods)
- Biochemical and molecular analysis (proteins content and enzymes activity)
- Behavioral analysis: Basso–Beattie–Bresnahan (BBB) rating scale, limb grip strength, Von Frey or Semmes–Weinstein, pinch reflex, temperature tests, foot slip, grooming, urinary bladder function, autonomic dysreflexia, balloon test.
- Neurophysiology (Electromyography)
- Imaging (MRI, Ultrasonography, X-ray)
- Cardiovascular evaluation
- Musculoskeletal evaluation
- Respiratory evaluation