Traumatic spinal cord injuries (SCI) are a catastrophic type of injury that disrupt many functions of daily life such as mobility, temperature regulation, sexual function, and bowel/bladder use. Approximately 80% of individuals who suffer from SCI develop neurogenic bladders, and subsequently require catheterization. Patients with sacral SCI have different neurogenic bladders than those with higher injuries; specifically, severing the peripheral innervation at the sacral level causes a non-contracting and low pressure bladder, without the scar tissue found commonly in higher injuries. This suggests that peripheral denervation decreases the incidence of non-compliant bladder complications. Bladders primarily have two uses - storage and voiding during urination. One common strategy to improve the storage function of neurogenic bladders is to denervate them with direct injections of Onabotulinumtoxin-A (ONA). However, this treatment is only applied after other treatments have failed, leaving time for significant damage to occur. In the current study, we propose to study the effects of direct ONA injections acutely after SCI. Our two aims are 1) to determine the treatment window for chemodenervation that best reduces bladder wall hypertrophy and fibrosis, and 2) to determine whether bladders remain compliant after chemodenervation. Using a rat model, we applied two treatments - SCI + Saline, SCI + ONA, with both saline and ONA directly injected into the bladder wall. A control group received laminectomy without injury. After treatment, we plan to measure bladder function using a urinary incontinence scale, as well as histological measurements of collagen deposition and muscle area to quantify bladder wall hypertrophy and fibrosis. We anticipate that early ONA injection (as defined in Aim 1) will be associated with less fibrous and more compliant bladders in the long term when compared with non-chemodenervated bladders. If our hypotheses are correct, we plan on getting IRB approval for a clinical trial.

Traumatic cervical spinal cord injury (SCI) results in a wide range of outcomes from partial paralysis to complete tetraplegia depending on the location of injury along the length of the cervical spinal cord. Importantly, there is a high density of motor neurons in the cervical region which are involved in important motor outputs such as breathing and hand function. The present study aims to minimize the secondary damage to the spinal cord after the primary insult, by addressing two substantial contributors to neuron death: first, surgical decompression is conducted to reduce local tissue swelling after injury, and second, administration of the metabolite oxaloacetate (OAA) to minimize excitotoxicity by stimulating glutamate transport away from injured neurons. We hypothesized that animals treated with decompression, OAA, or both, would have increased neuronal survival, general tissue sparing, and improved behavioral outcomes than those without treatment, and that combined treatment would be more effective than each individual treatment. We tested the treatments using a clinically relevant rat model for bilateral, moderately severe cervical spinal cord injury. Following treatments, we determined effectiveness by assessing animals’ forelimb function and quantifying motor neuron and white matter sparing in the injured tissue. Results consistent with the hypothesis would have meaningful impacts for future cervical SCI patients, as even a limited increase in tissue sparing in the cervical region have profound functional outcomes for patients’ independence and opportunities. Future studies will work to visualize parameters for segmental tissue at risk after acute injury in order to specify each patient’s treatment and maximize their opportunities for recovery.

Traumatic spinal cord injury (tSCI) often leads to a debilitating loss of sensory, motor, and autonomic function. Currently there are no treatment options available for patients with tSCI. Immediately following the initial trauma, microvessels in the spinal cord rupture, leading to hemorrhage within the spinal cord. Bleeding is a major contributor to a cascade of subsequent injuries, defined as secondary injury, such as swelling, inflammation, and oxidative stress, which results in the expansion of the initial injury. We hypothesize that enhancing blood clotting would limit secondary injury, and subsequently lead to better functional outcomes. To test this, we employed newly developed hemostatic nanoparticles (hNPs), which are designed to localize to the injury site and reduce bleeding in a contusion tSCI model in rodents. The hNPs or control nanoparticles were introduced intravenously within 3 minutes after the injury, and tomato lectin was injected at the end of the experiment to label all patent blood vessels. Clusters of hNPs were found within areas of hemorrhage and blood clot within the injury epicenter, and never seen co-labeled with tomato lectin, suggesting that hNPs were only within parenchyma in areas of active bleeding. Our unique ultrafast contrast enhanced ultrasound (CEUS) imaging was used to visualize hematoma size, local spinal blood perfusion and swelling in real-time. CEUS imaging data showed there was 50% reduction in hematoma size in hNPs treated animals compared to control. We also found significant reductions in hypoperfused volume (50%, p<0.05) as well as spinal cord swelling (30%, p<0.01) in hNPs treated animals compared to controls. Current studies are underway to 1) analyze real-time hemodynamic data obtained from ultrafast CEUS imaging, 2) evaluate chronic 3D blood flow imaging, and 3) quantify functional and histological outcomes from hNP treatment after tSCI.