Spinal cord injuries (SCI) have an immediate and devastating impact on movement control and various physiological functions. According to the numbers of the World Health Organization, between 250,000 and 500,000 new cases occur every year in the world. In recent decades, medical and scientific progress allowed to better understand these injuries. Surgical procedures, supportive measures and rehabilitation techniques have progressed, although no clinical study has been able to demonstrate the efficacy of a therapy for healing from a SCI. Since the central nervous system (CNS, which includes the brain and spinal cord) has a limited ability to regenerate after an injury, in most cases the damage is irreversible and half of the patients remain permanently paralyzed. Before learning the various biological and technological approaches used in the treatment of spinal injuries, let’s see some basic notions to introduce the topic.

Neurons and spinal cord

Neurons are the cells of the nervous system and have a particular structure. They consist of a body in which the nucleus is located and where all the main functions take place. From it, multiple small protrusions (dendrites) branch off and function as sensory antennas. Moreover, a long strand (the axon) transmits information (in the form of electrical impulses) to other cells in the body (muscles, other neurons). A point of contact between two neurons is called a synapse. Neurons are found in the brain and spinal cord. In particular, the latter contains only the bodies of neurons, while axons branch out throughout the body. Bundles of axons make up the nerves. They can transport information in three different ways: from the CNS to the periphery (efferent nerves, which innervate the muscles), from the periphery to the CNS (afferent nerves, with sensitive function) and in two directions (mixed nerves) if they transport information both from the CNS to the periphery and vice versa. According to the information transmitted, in the spinal cord it is possible to find motor neurons, which have the task of innervating the muscles, the sensory neurons that carry information to the CNS from the periphery and the interneurons that have neither a sensory nor a motor function, but allow communication between the neurons in a certain area. The spinal cord acts as an intelligent information-processing interface, capable of translating both sensory information from the body and input from the brain into muscle responses that meet various needs. In fact, communication occurs both descending (information coming from the brain and directed to the muscles through the motor neurons) and ascending (sensitive information directed from the periphery to the brain through the sensory neurons).

The spinal cord has a cylindrical shape, and is located inside a canal in the spine. Depending on the position in the body, it can be divided into four regions: cervical, thoracic, lumbar and sacral. From the spinal cord, 31 pairs of mixed nerves (spinal nerves) originate. Depending on the position, the spinal nerves reach different parts of the body: the cervical ones innervate the neck, shoulders and upper limbs, the thoracic nerves the intercostal and abdominal muscles, the lumbar and sacral ones the leg muscles.

Different types of injury

For a long time, it was believed that recovery from SCI required the precise reconstruction of neural connectivity present before the damage. However, decades of research have shown that this is not the case. In the brain, the loss of functionality of some synapses leads to the spontaneous formation of new ones derived from other connections that are still functioning. This spontaneous, structural and functional plasticity (which is very different from regeneration, in that it is only an adaptation mechanism) allows the brain to redirect neural information through alternative circuits to regain the functions lost due to the damage. As we will see, such a reorganization occurs spontaneously after an incomplete SCI.

SCIs are characterized by two phases: primary and secondary. The primary phase is immediate and derives from the direct, physical trauma, while the secondary one concerns the physiological and biochemical consequences of the trauma and develops for several weeks or months after the injury. In particular, the damage causes the local interruption of vascularization, which in turn causes acute hemorrhage and ischemia of the spinal cord. The rupture of blood vessels also causes the release of cytokines, vasoactive peptides and the accumulation of inflammatory cells that aggravate the pro-inflammatory state. Disruption of neural connections, on the other hand, leads to an excessive concentration of extracellular glutamate, which is toxic to cells and leads to their death. Immediate intervention is crucial to facilitate recovery from the injury and a transfer to a specialized center for SCIs within 24 hours from the accident is associated with more efficient recovery.

Following a SCI, communication between neurons “under” the injury and the brain is interrupted or reduced and, depending on the severity, the injury can be complete or incomplete. In the first case the communication is completely interrupted, in the second only partially and the paralysis will be as serious as the residual communication is reduced.

Following a complete SCI, all motor and sensory functions under the damage are lost. An incomplete lesion instead spares tissue bridges containing a variety of ascending and/or descending nerve pathways, depending on the location of the lesion.

The position of the lesion also has a role in determining the consequences: lesions close to the lumbar or sacral level cause a deficit in the control of the legs, the genitourinary system and the anal sphincter; those at the thoracic level also concern the muscles of the trunk; the cervical ones instead cause tetraplegia (paralysis of all the limbs).

Repairing complete lesions requires restoration of the neural connectivity, which needs invasive treatments. In contrast, incomplete lesions spare enough neural tissue to support communication through the lesion. These are often associated with a partial recovery of motility, which is also obtained by non-invasive treatments.

As we will see, there are several axonal growth mechanisms that can be activated (spontaneously or after induction) in response to an injury, which can be exploited in therapy.

Biological approach

In the event of incomplete injury, a therapeutic strategy is to induce a reorganization of the residual neurons. To achieve this, synaptic plasticity is stimulated. This can be achieved by the administration of serotonin, norepinephrine or dopamine agonists. This is supported by experiments conducted on rats, in which animals have undergone intermittent hypoxia (a transient reduction in oxygen levels). Lack of oxygen activates the neurons of the midbrain, which constitute the primary source of serotonin. A clinical study suggested that the combination of rehabilitation and intermittent hypoxia (which results in a greater presence of serotonin in the spinal cord) may improve walking in patients with incomplete SCI, compared to physical rehabilitation alone. However, confirmation of these results requires a phase 3 clinical study involving a large number of patients, not yet performed.

Instead, in the event of a complete SCI, communication through the lesion cannot occur spontaneously, but must be artificially induced. This can be achieved by stimulating axonal regrowth of neurons close to the lesion, for example through the administration of growth factors and the reconstitution of a hospitable microenvironment. Another approach consists in stem cell transplantation, which can differentiate both in neurons and in support cells in the damaged microenvironment. Although the premises were encouraging, it was observed that transplantation cannot achieve the desired long-term effects. In fact, although this therapy has acquired significant clinical importance, the transplanted cells do not survive for a long period at the injury site because of the unfavorable conditions.

Some evidence suggests that the combination of multiple therapeutic strategies promotes regrowth of axons through the injury. In addition, the use of biomaterials improves the survival of transplanted cells. Injectable and resorbable polypeptide hydrogels can provide temporary deposits for the prolonged release of growth factors, with significant benefits for axonal regrowth. The hydrogel and collagen networks can be designed to provide oriented structures that facilitate the alignment of the grafted cells and thus direct the correct regrowth of the axon. A very recent approach (from 2019) exploits the continuous projection micro-scale printing (μCPP) in order to recreate central nervous system structures, functional for various applications of regenerative medicine in the spinal cord. The three-dimensional printing of these structures makes the application available for any patient and any type of injury.

Technological approach

Like biological strategies, also technological ones aim to restore communication between the neurons above and below the lesion, or to bypass it by exploiting the intrinsic plasticity of the spared cells. The new technologies include exoskeletons for the lower and upper limbs (devices that align with the movement of the joints, supporting them), body weight support systems, functional electrical stimulation of the muscles and neuromodulation therapies of the bone marrow. These strategies are implemented with anti-inflammatory and neuroprotective pharmacological treatments, aimed at limiting the inflammatory process caused by the lesion and preventing the deterioration of the surviving neurons.

Among the technologies aimed at restoring communication between residual neurons (therefore we speak of incomplete lesions), it is worth mentioning transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS). The first allows, through a low intensity direct current transmitted by electrodes positioned directly on the scalp, a non-invasive stimulation that is not perceivable by the patient capable of determining prolonged changes in brain excitability. The second stimulates neurons through the creation of a magnetic field at brain level for a short period of time, and is also used to treat depression and attention deficit disorder (ADHD).

In the event of a complete injury, you can try to bypass the damage. For example, brain machine interfaces (BMI) require the association of assistive devices (exoskeletons) with a brain signal recording device. The recording device can be surgically implanted in the patient’s skull or placed noninvasively on the scalp. This receives brain signals, which are decoded and transformed into an instruction directed to the assistance device, which in turn controls the exoskeleton, allowing movement. In this way, the brain is able to communicate with the robotic device, bypassing the lesion.

Another promising strategy (currently the most advanced in the field) is the electrical epidural stimulation of the spinal cord, valid for both complete and incomplete SCIs located in the lumbar region. The device consists of an electrostimulator and a plate with 16 electrodes which is surgically implanted on the posterior structure of the bone marrow, in correspondence with the lesion. The electrical stimulus allows to amplify and transmit the incoming signal from the brain to the neurons under the lesion, making limb movement possible again. The stimulation of motor neurons occurs only when movement is expected. This spatio-temporal stimulation is the key innovation of this therapy, as it significantly improves the results obtained compared to continuous stimulation. In particular, the latter has effects on muscle activity, but does not allow locomotion, which instead is guaranteed by space-time stimulation. Already after a week, the spatio-temporal stimulation is able to re-establish the adaptive control of the paralyzed muscles during the walk. After a few months of rehabilitation, patients treated with this technique have regained voluntary control over paralyzed muscles and are able to walk or pedal in facilitated contexts, thanks to stimulation. The facilitated context, during rehabilitation, can be obtained through body weight supported treadmill training (BWSTT). A patient using this technology is supported by a harness suspended from a metal structure or from the ceiling. This reduces the weight on the feet while walking on the treadmill. The amount of support can be gradually increased or reduced as needed. The evidence indicates several benefits, including strengthening of impaired muscles, improving the speed and efficiency of walking and the treatment of secondary medical conditions such as spasticity, pain, changes in the cardiovascular system and metabolism and quality of life in general.