Authors: Sejal Pola, Harini Sivanandh Ramadass, Vishnupriya Ravindranath, Akanksha Saxena,, and Iris Zheng
Mentor: May Sin Ke. May is currently a doctoral candidate in the Department of Oncology at the University of Oxford.
Abstract
This review paper examines the current state of research on spinal cord injury (SCI), highlighting treatments such as corticosteroids, neuroprotective, neuroregenerative therapies and scaffolding. With major parts of the demographic suffering from SCI yearly, understanding the different types and phases of SCI is crucial for improving patient rehabilitation. This paper explores various research approaches in advancing current treatment strategies. For example, corticosteroids aim to reduce inflammation and secondary damage following SCI, providing immediate intervention to mitigate further injury. Scaffolding, by using biomaterials, creates a supportive structure that facilitates tissue repair and regeneration at the injury site. Neuroprotective agents, such as immunotherapy, work to protect neurons from further damage by targeting specific inflammatory responses. Furthermore, neuroregenerative modulations aid in stimulating the growth and repair of neural tissues, potentially restoring lost functions. In this review, we summarize the recent advances in SCI studies by assessing various in vitro, in vivo experiments and clinical trials. We discuss the different approaches used, highlighting the key benefits, drawbacks, and implications. We highlighted the various controversies and challenges that researchers face in identifying a definitive treatment for the condition and the possible directions SCI research could go in the future.
Introduction
Spinal cord injury (SCI) is a condition where the spinal cord undergoes physiological and chemical changes due to trauma or other damage. Depending on the impact of the damage, SCI can exist in multiple stages that range from the severing of axons to complete paralysis. Specifically, SCI has a primary and a secondary phase (Anjum et al., 2020). Primary injury is associated with a more acute form of the condition, resulting in fractures and dislocation of the vertebrae due to some form of sudden trauma. It is characterized by damaged nervous tissue and severed axons followed by the hemorrhage of blood vessels. Secondary injury comes from further deterioration due to biochemical and physiological changes in the spine. SCI research aims to overcome the many biological manifestations of secondary SCI, namely inflammation, apoptosis, cyst formation, and glial scarring. Cyst formation, also known as syringomyelia, describes the build-up of cerebrospinal fluid in spinal tissue which can become large enough to compress the nerves and halt the passage of information from the brain to the rest of the body (Goetz et al., 2021). Glial scar formation occurs as a response to the release of pro-inflammatory cytokines, which are signaling molecules that initiate inflammation. This leads to the accumulation of astrocytes (glial cells) at the injury site, forming glial tissue. While this natural mechanism is meant to protect the injury and prevent it from spreading to other parts of the spine, it inhibits axon regeneration and the repair of damaged neurons (Pang et al., 2021). As a result, continued scar formation can lead to a loss of motor function (Anjum et al., 2020). Further research is required to develop treatments that address these vital issues and prevent additional damage.
Global estimates show that approximately 15.4 million people were living with SCI in 2021 (World Health Organization, 2024). Recent estimates show that the annual incidence of traumatic SCI in the United States–largely due to motor accidents–was 54 cases per one million people (Jain et al., 2015). SCI is currently a heavily researched topic as there are about 324 total research/disease areas that are being funded in the United States with around $95 million research funds budgeted yearly (National Institutes of Health Research Portfolio Online Reporting Tools, 2024). Rat models are most commonly used for SCI research because of their similar injury response to humans (cystic cavities, glial scar formation, extracellular matrix (ECM) changes). Clinical trials evaluate SCI through the International Stands for Neurological Classification of Spinal Cord Injury (ISNCSCI) using the American Spinal Injury Association (ASIA) impairment scale summary score tests; this is the main measure for neurological outcome. Treating SCI patients can result in a heavy financial burden, with the estimated lifetime economic burden per individual ranging from $1.5 million to $3.0 million in 2021 (Diop et al., 2021). The national costs in the United States relating to SCI hospitalizations was estimated to be $1.7 billion in 2009 (Malekzadeh et al., 2021).
Limitations in Current Standard of Care
Although SCI is an injury that can be detrimental to its patient, there are only limited treatments that can alleviate the impacts of the injury. The lifetime rehabilitation costs for SCI adds to an estimated 6 million dollars annually (Xiao et al., 2019). The total financial impact, including medical expenses, rehabilitation, and other related expenses, is estimated to be 10 billion dollars, due to the rising cases of SCI annually (Carlson & Gorden, 2002). Therefore, the urgent development and research into SCI is essential.
The current standard of care for SCI patients revolves around surgical intervention, high doses of methylprednisolone (MP) sodium succinate (a corticosteroid/steroid used to reduce inflammation), and rehabilitation (Baptiste & Fehlings, 2007). Unfortunately, these methods of management are not nearly as effective; currently, 80% of patients with SCI are stabilized with surgery without further research into other outcomes over Aggressive Physical and Chemical Management (APCM) (El Masri, 2010). APCM refers to the alternative non-invasive methods of spinal injury care, rather than the preferred method of surgery. Therefore, further research into new methods is critical to improve the overall standard of living of patients who suffer from SCI. In terms of progression, scientists are researching and evaluating the effectiveness of surgical decompression in patients through the Surgical Treatment for Acute Spinal Cord Injury Study (STASCIS) Trial; Some discoveries have progressed from the preclinical to clinical stages (Baptiste & Fehlings, 2007). Although there have been some significant advancements, as discussed before, there are many limitations in the current standard of care for SCI. Due to diverse factors that are present in SCI treatment, such as differences in severity of injury and health status of patients, personalized medicine is essential to improve the success of therapy (O’Shea et al., 2017). Therefore, more research into SCI treatments can help to find more effective methods to combat SCI. Therapeutic approaches, neuroprotective and neuroregenerative strategies and 3D scaffolds are all promising remedies to alleviate the harmful impacts of traumatic SCI.
Current Areas of Research
Since SCI varies in its complexities, there are several therapies and approaches under consideration. Stem cell transplantation methods are being researched as a way to regenerate damaged nerve pathways and reduce the damage of SCI (Yamazaki et al., 2020). Neuroprosthetics and brain-machine interfaces utilize brain signals to operate prosthetics for paralyzed patients (Lorach et al., 2023). Immunotherapy targets the protective myelin sheath surrounding axons to aid in neuroregeneration (Saeed, 2023). Biomaterials like polymer scaffolds provide structural support to the spine and aim at rebuilding neural pathways (Qu et al., 2020). Corticosteroids aim for reducing inflammation and its harmful effects in the spine (Lee & Jeong, 2022).
There are multiple prevailing theories on SCI treatments that researchers continue to explore. Current investigation for treatments can be classified as neuroprotective or neuroregenerative (Ahuja, et. al, 2017). Neuroprotective approaches look towards protecting the spine and nervous tissues from further damage and deterioration. Neuroregenerative pathways aim for the regrowth and repair of damaged neurons, axons, and synapses. Researchers are also considering combination therapies to treat SCI, where multiple approaches are combined for better results. For example, non-pharmacological agents should be combined with pharmacological ones for long-term efficacy (Anjum et al., 2020).
Neural stem cells (NSCs) are cells that aid in cerebrospinal fluid regulation. They are found in the lateral ventricle of the brain, as well as a part of the hippocampus and the spinal cord (Shao et al., 2019). They are often used in treating SCIs due to their multipotent classification and their subsequent ability to differentiate into oligodendrocytes, astrocytes, and neurons. (Ruzicka et al., 2017; Shao et al., 2019). Neural progenitor cells (NPCs) are a type of neural cell which are able to differentiate into different types of cells, meaning they can be unipotent, bipotent, or multipotent. They are highly mobile and move around the rostral migratory stream to the olfactory bulb, where they differentiate. However, unlike stem cells, NPC’s proliferation is limited, and they are unable to self-renew (Zarco et al., 2019). Mesenchymal stem cells (MSCs) are also widely used in SCI treatment, due to their high availability, their positive effects, and their low immunogenicity (Dasari, 2014). MSCs are found in bone marrow, placenta, adipose tissue, umbilical cord, and amnion, making them abundant and easy to access. They are also highly effective in treating diseases and conditions associated with the spinal cord and central nervous system (Qu & Zhang, 2017; Shao et al., 2019). Bone marrow MSCs are also highly effective in treating SCI due to their ability to differentiate into osteoblasts, chondrocytes, chondroblasts, adipocytes, fibroblasts, and neural and glial cells (Luo et al., 2018). They are anti-inflammatory and immunosuppressive, enhancing their ability to aid in SCI treatment (Shao et al., 2019).
Results
The SCI repair treatments explored in this review are sectioned into four categories: neuroprotection, immunotherapy, neuroregeneration, and neuromodulation (Figure 1). Corticosteroids, a type of anti-inflammatory drug, reduces cell death in SCI models. Another approach is immunotherapy which has the potential to minimize inflammation (Nrg-1 immunotherapy) and prevent myelin-associated inhibition through vaccines that target such receptors (NgR and PirB). Neuroregenerative treatments through neural stem cells and have shown regeneration of neural cells and improvements in sensorimotor function; combined strategies of polymer scaffolds and stem cells induces regenerative properties while rehabilitative SCI treatment approaches through BMIs and neuroprosthetics have shown potential to restore function and muscle control to paralyzed SCI patients. The following sections will explore the various fields and treatment strategies for SCI repair.
Figure 1. Overview of SCI repair treatments. This review aims to summarize treatment methods of neuroprotection, immunotherapy, neuroregeneration, and neuromodulation for SCI repair.
Corticosteroids
Neuroprotective approaches, such as the use of corticosteroids, offer significant advancements that can help maximize the effectiveness of treatment. Corticosteroids are anti-inflammatory drugs used to treat rheumatologic diseases (inflammation of the blood vessels), where the body's defense system malfunctions and causes tissue damage. Specific corticosteroids include cortisone, prednisone and methylprednisolone. Steroids reduce the production of inflammation-causing chemicals and the function of white blood cells, helping to minimize tissue damage.
A study by Schröter et al. (2020) examined the effects of the corticosteroid MP on the proliferation of neural progenitor cells (NPCs) in the spinal cord following SCI in mice. In this experiment, adult female C57BL mice were deeply anesthetized and subjected to a thoracic dorsal hemisection to simulate SCI. The mice received 30 mg/kg of the anti-inflammatory drug methylprednisolone (MP) immediately after the injury and again 24 hours later. The researchers measured the response of microglia and macrophages 7 days after the injury, as well as the proliferation and differentiation of NPCs at two time points, 7 and 28 days post-injury, as represented in the following graphic (Figure 2).
Figure 3. Effect of methylprednisolone (MP) on cell proliferation and immune response after SCI, with time points, and the relative measure of NPC proliferation. The X axis represents the time points during injury when methylprednisolone was administered and the effects it had on immune response. The Y axis represents the relative measure of NPC proliferation based on this dependent factor (Schröter et al. 2020).
The results from this study found that MP treatment significantly reduced the number of NPCs actively dividing and increasing shortly after the SCI, as reflected by the graphic (Figure 3). Specifically, MP treatment led to a decrease in both the immune response (activation and proliferation of microglia and macrophages) and the number of cells that could potentially develop into myelin-producing cells otherwise known as oligodendrocyte progenitor cells (OPCs) after SCI. Ultimately, MP treatment did not affect the proliferation of cells that started dividing later in the recovery process, proving how the inhibitory effect of MP on cell proliferation was more pronounced in the early stages (acute phase). Building on the positive results of this experiment, early administration of MP may reduce initial tissue damage and inflammation in humans. Combining MP with therapies that encourage later cell proliferation could enhance recovery, but more clinical trials are needed to optimize combination strategies with MP use for human patients.
Another study conducted by the Nam lab found electroacupuncture and corticosteroids to be effective in treating partial paralysis caused by SCI in dogs (Table 1). Electroacupuncture is a specialized type of acupuncture that uses electrical impulses of various frequencies and intensities through acupuncture needles. Electroacupuncture combines the traditional ideas of acupuncture with electrical stimulation which helps to enhance the effects of acupuncture, potentially improving its ability to modulate pain, reduce inflammation, and promote healing. By stimulating nerves and influencing the release of neurotransmitters and endorphins, electroacupuncture can help to regulate pain and inflammation. When used together, electroacupuncture and corticosteroids can enhance pain relief and improve motor function recovery, by reducing inflammation.
To investigate the effectiveness of these treatments, the researchers selected twenty healthy dogs and induced SCI by compressing approximately 25% of the spinal cord’s width. As a result, the dogs lost sense of the position of their limbs and the ability to perform the reflexive action of extending their legs to support their weight. To form both the control and experimental groups, the dogs were divided into four groups based on the treatment administered: corticosteroids (Group A), electroacupuncture (Group B), a combination of corticosteroids and electroacupuncture (Group AB), and a control group (Group C). The average recovery times for body awareness and senses, and extensor postural thrust for each group are summarized in the table below:
Table 1. Average recovery time for different treatments (Yang et al., 2019).
Group | Treatment | Average Body Recovery Time (Body Awareness and Senses) [Days] | Average Recovery Time (Extensor Postural Thrust) [Days] |
A | Corticosteroid | 21.2 | 12.8 |
B | Electroacupuncture | 19.8 | 13.8 |
AB | Corticosteroid + Electroacupuncture | 8.2 | 5.4 |
C | Control | 46.6 | 38.2 |
Examinations were performed daily to monitor progression until motor functions returned to normal, and somatosensory evoked potentials (SEPs) were measured to provide accurate evaluations of spinal cord motor function. Somatosensory evoked potentials (SEPs) are a type of neurophysiological test used to measure the electrical activity in the brain and spinal cord in response to sensory stimuli, such as electrical stimulation. The recorded signals are analyzed to determine the speed and integrity of the sensory pathways, which can help to provide information about the severity and potential recovery of the injury. According to the experimental results (Figure 3), it was found that Combination Treatment (Group AB) resulted in the shortest recovery times for both body awareness and balance, indicating that combining corticosteroids with electroacupuncture is more effective than using either treatment by itself. Additionally, Control Group (Group C) showed the longest recovery times, highlighting the necessity of active treatments to improve recovery outcomes. Between corticosteroids (Group A) and electroacupuncture (Group B) alone, recovery times are relatively similar, though the combination therapy shows a clear advantage. Across all groups, SEP conduction velocities significantly decreased post-SCI (p<0.05), but then showed a tendency to return to normal as motor functions improved (Yang et al., 2019).
Combining corticosteroids with electroacupuncture can aid in accelerating the recovery of SCI patients, potentially offering a more effective treatment. This approach might improve rehabilitation outcomes and enhance postural control. Additionally, using SEPs could help monitor recovery progress and treatment more efficiently in human patients. Again, more clinical trials need to be conducted to confirm such benefits.
Neuroprotective Agents
Current research has found that the neuroprotective agents, riluzole and minocycline, have been effective for treating spinal cord injuries. Riluzole and minocycline have shown results such as reduced inflammation and increase in motor abilities (Figure 3). They both have shown an increase in motor score, however, the scores were taken only from two studies, so further research should be done pertaining to how these drugs increase motor score. Riluzole is a sodium channel blocker that indirectly prevents cellular death and reduces excitotoxicity (Ahuja et al., 2017). A phase I trial was conducted to test riluzole and a gain of 15.5 points in motor score for patients with cervical injuries was found for the riluzole group of 24 patients over the comparison registry group of 26 patients (Shah et al., 2020). Additionally, results from pre-planned secondary analyses of a multi-center, randomized, placebo-controlled, double-blinded trial showed significant functional recovery gains in all subgroups of cervical SCI subjects treated with riluzole (Fehlings et al., 2023).
Minocycline is a modified form of tetracycline and it has shown benefit in animal studies and clinical trials. Minocycline reduces oligodendrocyte apoptosis (loss of cells that produce myelin sheaths that protect axons) and reduces local inflammation (Ahuja et al., 2017). In animal models, it has been shown that minocycline decreases neuronal apoptosis and has anti-inflammatory effects. In randomized controlled Phase II clinical trials, minocycline was associated with 14-point gain in motor score over placebo in patients with cervical spinal cord injuries (Shah et al., 2020). In another phase II placebo-controlled randomized trial, minocycline in acute SCI showed that patients with cervical motor-incomplete injury had a greater tendency towards improvement; with 14 motor points greater than those receiving the placebo (Casha et al., 2012). Overall, these neuroprotective agents have shown benefits which shows that they would be a good treatment for spinal cord injuries.
Figure 3. Comparison of Motor Score Gain between Riluzole and Minocyline. (a) The x-axis represents the type of drug, and the y-axis is the increase in motor score. The riluzole shows a 1.5 point increase compared to the minocycline (Shah et al., 2020).
Immunotherapy
Studies on immunotherapy treatments on spinal cords have shown that they are beneficial for healing spinal cord injuries. Research studies focused on inflammatory responses to secondary damage to the spinal cord, have suggested that identifying the signaling pathways of the response can be useful in creating neuroprotective and regenerative mechanisms, which could promote the healing of the spinal cord (Saeed, 2023). For example, a damaged myelin sheath is one of the root causes of muscular spasms in a SCI. However, preclinical evidence from rat models have shown that immunizing anti-Nogo antibodies stimulates the regeneration of the myelin sheath and lowers muscle spasms (Saeed, 2023).
A different study tested Nrg-1 (Neuronal derived Neuregulin-1) immunotherapy, and its effect on treating spinal cord injuries. This study was conducted on three groups of rats: uninjured, rats that received the vehicle solution, and rats who received the Nrg-1. A vehicle solution is a substance used as a carrier or solvent for a drug or intervention that is being tested. In a specific part of the study, the researchers were observing differences in macrophages (Alizadeh et al., 2018). Macrophages are a type of white blood cell that kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. Compared to both vehicle and uninjured rats, Nrg-1-treated animals showed a significantly higher number of M1 macrophages (Alizadeh et al., 2018). Overall, this study shows that Nrg-1 immunotherapy treatment promotes immune boosters while lessening pro-inflammatory cytokines and chemokines.
Another study tested a nucleic acid vaccine which targeted the Nogo-66 receptor (NgR) and the paired immunoglobulin-like receptor B (PirB), as an immunotherapy treatment for spinal cord injuries in rats (Lu et al., 2019). The Nogo-66 receptor and paired immunoglobulin-like receptor B are common receptors for myelin-associated inhibitors. The PcDNA-NgR-PirB vectors were used as controls, and the rats were given 100 μg of a nucleic acid vaccine. The results showed that the titer of rats immunized with pcDNA-GMCSF-NgR-PirB as well as pcDNA-NgR-PirB was significantly higher than that of unimmunized SCI rats, and the average antibody titer in rats immunized with pcDNA-GMCSF-NgR-PirB was significantly higher than that immunized with pcDNA-NgR-PirB (Lu et al., 2019). The study showed that vaccination targeting the Nogo-66 receptor and paired immunoglobulin-like receptor B could promote nerve regeneration at the site of injury, and promote functional recovery after SCI. In summary, the promising results from immunotherapy indicate its potential to heal spinal cord injuries.
Neurogeneration
Injury to the spinal cord is irreversible once it has occurred, due to the inability of the adult central nervous system to spontaneously regenerate. Therefore, it is imperative to research SCI treatments that promote reconstruction of the spinal cord and improvement of the sensorimotor and autonomic functions the uninjured spinal cord is responsible for. A promising method for reconstruction of the spinal cord is that of stem cell transplantation. The most integral use of stem cell transplantation for SCI is to reconnect disrupted axons, as well as replace lost neurons and glia (Lu et al., 2017). To fulfill these purposes, neural stem cells (NSC) can easily be utilized, due to their ability to differentiate into neurons and glia. Furthermore, these differentiated neurons can serve as interneurons to reconnect severed axons. The NSI-566 cell line is a stable neural stem cell line derived from a human fetal spinal cord and epigenetically multiplied. It is commonly used in research involving the treatment of SCI and amyotrophic lateral sclerosis.
One study utilized a NSI-566 cell line in animal models with SCI and showed a statistically significant improvement in neurological function, both sensory and motor (Curtis et al., 2018). There was also an improvement in muscle spasticity, as well as proof of functional synaptic coupling between grafted NSI-566 cells with the host spinal neuronal circuitry in rat models (van Gorp et al., 2013; Curtis et al., 2018). In a long term (9-10 months) study with 90 nude rats with spinally grafted NSI-566 cells, no deterioration of neurological function was identified (Curtis et al., 2018).
Additionally, in another study whose aim was to evaluate the efficacy of stem cell transplantation for SCIs, it was proven that stem cell transplantation increased the ASIA lower limb light touch score, lower limb pinprick score, and notably reduced residual urine volume as compared to rehabilitation therapy. However, it did not significantly improve motor score or daily living activity function (Zhang et al.. 2018). Another type of stem cell being used in stem cell transplantation are MSCs. MSCs have shown promising results in anti-inflammatory properties in cell environments, specifically in rats. MSCs proved to aid in promoting anti-inflammatory phenotypes in macrophages (M2) and suppressing the spread of lymphocytes before sustaining regeneration (Cofano et al., 2019). In each study, neural, sensory, and motor function has improved as a result of transplantation. The transplantation method is a reliable and sound treatment for SCI (Cofano et al., 2019). However, MSCs need to be used in combination with other treatment strategies.
Biomaterials
Biomaterials have been under intense investigation, with success in engineering biodegradable scaffolds that structurally support the spinal cord and replace parts of the lost extracellular matrix. 3D polymer scaffolds have shown regenerative ability to address mechanisms of secondary injury such as prevention of glial scar formation and the promotion of neuronal and glial cell growth and differentiation in addition to improvements in motor function.
A scaffold is a temporary platform mainly to provide support to the injured areas and serve as a promoter region for cell growth and proliferation (Perez-Puyana et al., 2020). In these studies, there has been evidence for promising treatments using biomaterial scaffolds both alone and in combination with stem cells transplantation.
A study was done on the combined application of human fetal NPCs seeded onto a poly(glycolic acid) (PGA) based scaffold to form a hNPC-PGA complex. This stem cell-scaffold complex was transplanted into 60 adult rats with SCI and compared with scaffold-alone, cell-alone, and vehicle control groups. 20% of the rats showed that the hNPC-PGA complex not only appeared to refill the hemisection cavity but also became integrated into the injury (Shin et al., 2018).
Moreover, hNPC-PGA transplanted rats had a significantly decreased total lesion (abnormal tissue) volume compared to the control group, which indicates possible improvement in motor function. The engrafted hNPC donor-derived cells also differentiated into neuronal cells, however more than 80% remained as immature neural precursor cells. Through GFAP (glial fibrillary acidic protein) staining, the lesion epicenters of groups containing scaffolds and the newly formed tissue showed significantly lower density than the control group, suggesting that they may function in reducing astrogliosis and glial scar formation (Shin et al., 2018).
Behaviorally, the hNPC-PGA implantation allowed for significantly greater functional recovery in the ipsilateral (same side) and contralateral (opposite side) lesioned hindlimbs from 14 days onward post-transplantation compared to other groups (Shin et al., 2018). These results are further supported by the next study.
Another study was done on the transplantation of a mixed (poly(lactic-co-glycolic acid) (PLGA) scaffold seeded with NSCs into the hemisection of 50 adult rats with SCI; they were compared with scaffold-alone, cell-alone, and lesion control group. The NSC-PLGA complex group showed promotion of long term improvement in function compared to a lesion-control group. Both ipsilateral hindlimbs of the rats were affected, yet recovered because of the cell-scaffold complex implantation. The NSC-PLGA and scaffold-alone group on average had scores reflecting normal walking and occasional hindlimb coordination. Similar to the previous study reviewed, not only was the rate of improvement for the complex significantly greater, but the walking score was also higher for all time after 14 days for rats implanted with NSC-PLGA complexes (Teng et al., 2002).
Additionally, groups containing the scaffold showed little lesion residue, with some appearing to have newly formed tissue at the injury epicenter. Whereas the groups without scaffolds had long residual lesions that covered most of the cord; they exhibited atrophy at each end of the injury; scar tissue and cysts could be seen in some of the cell-alone and lesion control groups (Teng et al., 2002).
Shifting to a scaffold-alone approach, a 24 month follow up clinical trial was based on a previous 6-month data study conducted by the In vivo Study of Probable Benefit of the Neuro-Spinal Scaffold for Safety and Neurological Recovery in Patients with Complete Thoracic Spinal Cord Injury (INSPIRE). 16 patients with complete thoracic SCI underwent acute implantation of a polymer Neuro-Spinal Scaffold (NSS) and were evaluated. 7 out of 16 (44%) patients had improved 1 or more ASIA Impairment Scale grade by 6 months, and some showed further improvement at the end of the 24 months while none of the patients showed signs of neurological deterioration (Kim et al., 2021).
Both the first and second study reveal the success of biomaterial scaffolding in combination with stem cells to induce neural repair, protection, regeneration, and locomotion function recovery. As shown in the third study, even polymer scaffolds alone may promote neurological improvements in human SCI patients. The investigation into biomaterial scaffolds combined with application of other fields such as cellular transplantation provides a pathway for other multidisciplinary approaches for future treatments or other neurological diseases.
Neuromodulatory Interventions
Recent studies have shown that neuromodulatory interventions, such as brain-machine interfaces (BMIs) and neuroprosthetics, can be a feasible method for the rehabilitation of SCI patients that have some form of paralysis. BMIs utilize electrodes connected to the brain which record signals. The signals can then be decoded into commands relating to motion, which can power prosthetic limbs.
A 2021 trial showed that BMI systems are able to restore voluntary control of the forelimbs of rats with severe cervical SCI, with an average improvement of 38% compared to a 21% improvement when the system was off. The researchers also measured for performance efficiency by observing how well the rats could press a lever to get rewards. With the BMI system on, the animals received 11.5 rewards per minute as opposed to 6.8 rewards per minute when the system was off (Tian et al., 2023; Samejima et al., 2021). A 2016 pre-clinical trial showed that BMI systems are able to decode brain signals into the correct intended motion in healthy subjects and SCI patients. Approximately 84.44% of the trials were correctly decoded by the BMI in healthy subjects, while 77.61% of the trials were correctly decoded in the SCI patients. The same trial illustrated the average time in seconds from the auditory cue to the prosthetic movement in the subjects, which was 1.07 seconds for the healthy patients and 1.35 seconds for the SCI patients (López-Larraz et al., 2016).
Rather than testing simple hand movements such as grasping and reaching, researchers in a 2021 study wanted to test quick, dexterous behaviors such as handwriting and touch typing in paralyzed patients using a BMI. The study participant with a paralyzed hand achieved a typing speed of 90 characters per minute with 94.1% raw accuracy, which is comparable to the average typing speed of individuals in the participant’s age group (115 characters per minute, Tian et al., 2023; Willett et al., 2021). A 2016 clinical trial allowed an individual with chronic tetraplegia to complete multiple activities such as standing, hip flexions, walking, climbing stairs, and traversing complex terrains with a surgically implanted brain-spine interface (BSI). In the one year study by Lorach et al. (2023) the patient was able to walk with crutches without the BSI, ultimately achieving improved neurological recovery.
All of these results show that BMIs are potential solutions for bringing back motor function to paralyzed SCI patients. The trials illustrated the system’s ability to help the participants engage in various activities that they were not capable of performing before (Tian et al., 2023; Samejima et al., 2021; López-Larraz et al., 2016; Willett et al., 2021; Lorach et al., 2023). However, researchers need to consider the challenges with this system before it is widely available, such as its decoding accuracy and false positives. The second trial showed high rates of false positives–times when the BMI system incorrectly detected movement when no movement was intended–during periods of rest in both the healthy subjects and SCI patients, which were generated in more than 60% of the trials (López-Larraz et al., 2016). This indicates that the BMI system needs improvement to reduce false positives.
Discussion
This review highlights several promising areas of research towards developing effective treatments for SCI. Immunotherapy is one such promising area, yet significant limitations hinder its clinical application. Most studies have been conducted on rats, making it difficult to generalize findings to human patients. Despite advancements in preclinical trials, safety and delayed effects remain major challenges for translating these strategies to clinical settings. Currently, immunotherapy treatments lack established safety and efficacy parameters, preventing significant clinical outcomes. Comprehensive studies are required to ensure the safety and efficacy of these strategies, minimizing risks of neurological damage (Lu et al., 2016). Although immunotherapy holds significant potential, rigorous clinical trials and extensive safety evaluations are necessary before it can be widely applied in hospitals.
The design and fabrication of scaffolds present another area of research with both potential and limitations. The efficacy of scaffolds varies depending on the combination of synthetic and natural materials used, with some materials potentially causing toxicity and inflammation in patients. In some studies, small sample sizes and lack of a control group hindered the clear determination of polymer scaffolds' benefits for SCI patients. The study on hNPCs-PGA complexes showed promise in repopulating cells in damaged spinal cord regions but faced challenges with tissue mass volume inhibiting cell differentiation. Similarly, the combination transplant of neural stem cells and scaffolds showed improvement in rats but may not fully translate to humans due to biological differences.
Neuroprosthetics and brain-machine interfaces (BMIs) are promising for assisting in SCI rehabilitation but require further study before widespread use. Most trials reviewed involved human patients, strengthening the case for BMIs in clinical settings. However, larger sample sizes and longer study durations could have produced stronger results. A 2016 clinical trial showed high false positive rates, indicating a need for further development to increase BMI systems' reliability and convenience (López-Larraz et al., 2016). Despite these challenges, these studies demonstrated the feasibility of BMIs in restoring voluntary motor control in SCI patients, even with chronic paralysis.
Corticosteroids offer many benefits for SCI research but come with significant health risks. They can cause osteoporosis, fractures, osteonecrosis, and a decline in bone mineral density, increasing fracture risk. Corticosteroid intolerance or resistance in some patients necessitates new treatment forms. The suppression of the hypothalamic-pituitary-adrenal (HPA) axis by corticosteroids can lead to adrenal insufficiency, requiring careful medication tapering. Long-term use is associated with increased risks of glaucoma, cataracts, skin thinning, and striae, impacting patients' quality of life. Because of the many benefits associated with corticosteroids, researchers are aiming to develop safer alternatives to be implemented into SCI patients.
Stem cell transplantation shows promise for SCI treatment but faces limitations. The field is relatively new and subject to change, with many unknowns. While studies on mice and rats have shown promising results, human trials are lacking. Methods used for animal transplantation are not always suitable for humans, potentially causing spinal cord tract damage, infection, and secondary injury. Human clinical trials must remain the final aim, as the benefits observed in animal studies do not always translate to humans. Additionally, there is uncertainty about the optimal number and source of cells for transplantation. More research is needed on post-implantation treatment, immune suppression, and the long-term effects of stem cell transplants in human models before it can become a viable treatment for SCI in real patients (Cofano et al., 2019; Zhang et al., 2017; Abbaszadeh et al., 2018).
While the research into SCI treatments is promising, significant limitations remain. Translational challenges, safety concerns, and the need for extensive clinical trials hinder the implementation of these treatments in human patients. Continued research and development are crucial to overcoming these obstacles and making effective SCI treatments a reality.
Future Research
SCI remains a complex and challenging medical condition as it is unique from patient to patient. As a result, it lacks a definitive treatment due to the different types and severities of injury. While the various approaches discussed in this review show promise for treating the distinct aspects of the condition, further research and clinical trials are necessary to provide insight into more viable solutions.
One of the primary challenges in SCI research is translating rat studies into human models. For example, much of the research on immunotherapy, stem cell transplantation, and biomaterials have utilized rats. While these trials have shown promising results such as reduced inflammation, improved immune system, increased motor skills, and nerve regeneration, these results are often incomparable in accuracy when applied to human models due to physiological differences. The lack of human clinical trials renders it difficult to implement this treatment into hospitals as there is insufficient data. Therefore, future research should focus on conducting more studies on human models to ensure the safety and efficacy of these treatments.
Neuroprotective and neuroregenerative approaches, such as corticosteroids, are viable and promising approaches that have already shown positive results in numerous tests. Combining them allows for curated strategies that can be personalized to address the unique needs of each SCI patient. For instance, while polymer scaffolds have been shown in various studies to cause increased neuronal growth, behavioral recovery, and enhanced axonal regeneration, future research should consider the development of smart biomaterials integrated into scaffolds to match the mechanical properties of central nervous system (CNS) tissue. This may allow researchers to confidently declare the regenerative properties of polymer scaffolds in SCI. Furthermore, researching further into scaffold-stem cell complexes—where neural stem cells can be genetically modified to alter certain SCI-related diseases—may be a flexible tool for SCI repair (Shin et al., 2018). Therefore, future research into combination therapies will be a pivotal step in maximizing recovery and improving outcomes in SCI patients.
Stem cell transplantation is another approach that shows promise for SCI treatments. The exact quantities and cell types for maximum efficacy have not been found yet, so future research should consider testing other stem cell sources in different quantities, which may optimize its neuroregenerative properties and facilitate the recovery process. Overall, through an expansion of the field and an increase in experimentation and studying, stem cell transplantation can prove extremely helpful for patients suffering from spinal cord injuries.
Neuromodulation is another important area of research. Neuroprosthetics and BMI studies should test for long-term reliability and independent, at-home usage to develop systems that are convenient and user-friendly. Further testing on decoding accuracy can lead to more precise detections and better quality overall. Perfected BMI systems offer SCI patients the possibility of regaining the movement they lost, giving them a chance to restore a crucial part of their lives.
Future trials involving SCI patients should look towards addressing the issues of the most chronic forms of SCI, like tetraplegia. Long-term follow-up studies on these patients allows researchers to focus on the quality of life and psychological outcomes of their subjects. This information ultimately allows SCI research to not only develop more conclusive solutions but consider patient satisfaction. All in all, the future of SCI research lies in long-term human clinical trials, combination therapies, and more focus on patient satisfaction, among other things. The approaches described in this review hold significant potential for SCI treatment.
Conclusion
In this review, we provide a summary of various repair strategies for SCI including neuroprotective and neuroregenerative treatments, immunotherapy, and neuromodulatory interventions. Given the unpredictable nature in the physiological and chemical impacts of traumatic SCI, this review emphasizes the importance of using treatments to target the secondary effects found in these studies such as inflammation, apoptosis, cyst formation, and glial scarring. We further provide insights into treatments with possible rehabilitation and motor function improvement after SCI. These repair treatments have shown to promote neuroprotection, neuroregeneration, and overall neurological and motor function improvement across the studies. More clinical trials are required to further understand the efficacy and safety of these treatments especially for combinative treatment strategies to create personalized treatment plans that address the complex elements of SCI across patients of all demographics. With the surge of recent advancements in the medical and technological field, promising treatment will be closer to reality than a near future.
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