A spinal cord injury (SCI) involves damage to the nerves that transmit signals between the brain and the body, extending from the lower brain through the lower back. This damage, whether direct to the spinal cord or surrounding vertebrae, can lead to temporary or permanent changes in sensation, movement, strength, and various bodily functions below the injury site. The spinal cord’s structure, with its white matter tracts for signal transmission and central gray matter housing neuronal cell bodies, makes any disruption impactful on mobility and quality of life. SCI is a debilitating neurological condition due to the challenges of its repair.
Understanding Spinal Cord Damage
Spinal cord injuries involve a primary damage phase, characterized by mechanical disruption of neural tissue, hemorrhage, vascular damage, and direct injury to axons and myelin sheaths. This initial trauma can result from contusions, partial or complete severing of the spinal cord, bone fragments, and tearing of spinal ligaments. These events, including cellular necrosis and blood-spinal cord barrier disruption, occur within minutes of the injury.
Following the primary injury, secondary damage unfolds, disrupting the spinal cord microenvironment. This phase involves inflammation, cell death (including necrosis and apoptosis of neurons and oligodendrocytes), demyelination, and glial scar formation. Immune cells infiltrate the injury site, and activated glial cells, such as astrocytes and microglia, secrete toxins and cytokines, further damaging tissue initially spared from mechanical trauma. These responses inhibit regeneration, leading to persistent neurological deficits and axon retraction.
Current Approaches to Care
Acute care for spinal cord injuries focuses on stabilizing and decompressing the spine, often through surgery, to minimize further damage. Transportation to a specialized SCI center is crucial, as prompt treatment can reduce secondary complications and improve outcomes. While current guidelines consider methylprednisolone use within eight hours of injury for 24 hours, evidence supporting its beneficial effects on neurological recovery remains limited.
Pharmacological interventions in the acute phase of SCI primarily manage neurological symptoms and secondary complications, rather than directly enhancing neurological recovery. Patients receive various medications, including narcotics, analgesics, antibiotics, and antithrombotics, to address pain, infections, urinary tract dysfunction, and deep venous thrombosis. This often leads to polypharmacy.
Long-term care for individuals with SCI involves comprehensive rehabilitation strategies tailored to the injury’s severity and location. Physical and occupational therapy are central, focusing on maximizing functional recovery, improving mobility, and managing symptoms. Rehabilitation also incorporates assistive devices to enable individuals to live independently.
Emerging Repair Strategies
Current research explores various approaches to promote regeneration and restore function after SCI.
Stem Cell Therapy
Stem cell therapy involves transplanting different types of stem cells, such as neural stem cells (NSCs) or mesenchymal stem cells (MSCs), to replace damaged cells, provide trophic support, or modulate immune responses. NSCs are multipotent cells capable of differentiating into neurons, astrocytes, and oligodendrocytes, the main CNS cell types. These cells can survive, migrate, and differentiate at the injury site, potentially remyelinating damaged axons and replacing lost cells.
Gene Therapy
Gene therapy offers another approach by delivering specific genes to the injured spinal cord to promote axon growth or reduce inhibitory factors. For instance, genetically modifying stem cells to express neurotrophic factors like neurotrophin-3 (NT-3) or brain-derived neurotrophic factor (BDNF) shows promise in promoting axonal regeneration. This approach aims to create a more permissive environment for nerve repair by directly influencing gene expression within the spinal cord.
Biomaterial Scaffolds
Biomaterial scaffolds are engineered materials that bridge gaps in the injured spinal cord and provide structural support for nerve regeneration. These three-dimensional structures mimic the extracellular matrix of the spinal cord, facilitating cell adhesion, migration, proliferation, and differentiation. Scaffolds can also serve as carriers for delivering stem cells, growth factors, or drugs to the injury site, releasing therapeutic agents in a controlled manner. For example, combining hydrogels with NSCs and nanoparticles can reduce neuroinflammation and promote neuronal differentiation.
Neuroprotective Agents
Neuroprotective agents are drugs designed to protect surviving neurons and minimize secondary damage. Researchers are investigating compounds that can block growth-inhibiting molecules that appear after injury, allowing natural repair mechanisms to function. These agents aim to create a more favorable environment for neural repair by mitigating harmful processes after injury.
Overcoming Repair Obstacles
A major hurdle in spinal cord repair is the formation of the glial scar, which acts as both a physical and chemical barrier to axon regrowth. This scar, composed of reactive astrocytes, fibroblasts, and other glial cells, forms around the injury site to contain inflammation and limit damage spread. In its mature state, it becomes a dense, inhibitory structure that prevents axons from growing across the lesion.
The limited intrinsic regenerative capacity of adult central nervous system neurons poses a challenge. Unlike peripheral nerves, neurons in the adult spinal cord have a poor ability to regrow axons after injury. This inherent lack of regenerative drive contributes to the chronic failure of functional recovery.
The presence of inhibitory molecules within the myelin debris and extracellular matrix at the injury site repels growing axons. Molecules such as chondroitin sulfate proteoglycans (CSPGs) and myelin-associated glycoprotein (MAG) are upregulated after SCI and directly impede axon outgrowth. These molecular barriers make it difficult for regenerating axons to navigate the injury site and re-establish connections.
Chronic inflammation persists in the injured spinal cord, contributing to ongoing tissue damage and hindering repair. While an initial inflammatory response is part of wound healing, prolonged inflammation leads to the continued release of harmful cytokines and reactive oxygen species that can cause further neuronal loss and axon retraction. This sustained inflammatory environment creates an unfavorable microenvironment for regeneration, making functional recovery difficult to achieve.