Spinal cord injury (SCI) is well known as severely disabling injury that can result in long term neuro-logical impairment and great impact in social and economic aspect of the patients. Patients are usually rendered paraplegic or tetraplegic related to the sen-sory and motoric deficits. The most lethal compli-cation of SCI is impairment of bladder function, car-diovascular problems, and intestinal flora disturbances so the advanced therapeutic approach and strategies is very important to overcome these issues (Kader et al., 2018). Direct mechanical damages and secondary in-juries are the underlying mechanisms of SCI. Verte-bral fracture and dislocation is the main cause of direct mechanical damages leading to SCI. Dislocated discs or bone fragments can cause compression and con-tusion of the spinal cord. Secondary injuries leading to SCI can be related to inflammation, swelling, and neural apoptosis of the spinal cord (Kakulas et al., 2015). Besides that, another condition such as oxi-dative stress and disturbance of electrolyte also can lead to SCI. Some other condition can cause both pri-mary, and also secondary SCI such as demyelination, severe tissue destruction, Wallerian degeneration, axo-notmesis, syringomyelia, and formation of glial scar. There were some approach and strategies that have been developed and proposed to this condition, in-cluding surgery techniques, medications, and rehabi-litation. But, there were still questions regarding the efficacy of the treatment options (Xu et al., 2019). 

Recently, the standard of care for acute SCI is surgical treatments which mainly aim to spinal cord decom-pression and rehabilitation (Sunshine et al., 2017). However, there is still no neuroprotective and regene-rative modalities that is effective and useful. High-dose methylprednisolone has been proposed to have beneficial effects in patients with SCI, but the consensus on the efficacy of this approach is still unclear (Qin et al., 2018).  The clinical use of stem cell transplantation has become new trend in these decade and some studies reported its effectiveness in treating SCI in animal models. Some variety of stem cells which consist of neural stem cells, mesenchymal stem cells (MSCs), Schwann cells, embryonic stem cells, and induced pluripotent stem cells have been used and developed for transplantation. Among these stem cell variety, MSCs have been known for its im-portance in repairing the damaged spinal cord (Muhe-remu et al., 2016). Beside their superiority in differe-ntiation and replacement for the damaged cells, MSCs also secrete many neuroprotective factors and cyto-kines, including brain-derived neurotrophic factor (BDNF), glial-cell-line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VE-GF). The fore mentioned factors had important roles in improving regeneration of neural tissues, promoting axon growth, and repairing damaged neurons. Cur-rently, the outcome of MSCs transplantation to treat SCI in animal models have been verified (Abbasi et al., 2021; Cho et al., 2009) . 

Despite of its effect on animal models, the outcome of MSCs in treating SCI in humans is still questionable. No review study has extensively evaluated the out-come of MSCs for SCI treatment. These studies will discuss previous studies investigating the outcome of stem cell transplantation usage in treating patient with SCI.

Review of Literature

Search strategy

This systematic review was arranged based on the  PRISMA guideline (Fig. 1). 

Fig. 1:  Flow diagram describing the strategy for conducting this study based on PRISMA guideline.

Inclusion criteria

The inclusion criteria were outcome of stem cell trans-plantation for the management of SCI. Case series and case reports were also included in this review.  Due to the limited number of studies, we did not establish restriction for demographics of the patients, though some reports and literatures not in English were ex-cluded. Study that focus in rat study of stem cell transplantation and systemic review study are excluded from this review (Table 1).

Table 1: The criteria of inclusion & exclusion according to population, intervention, comparison & outcome.

Quality evaluation

After the search was performed, all authors screened to find studies which eligible. The all authors read the titles and abstracts and choose the article according to the inclusion criteria. Then, all authors continued to screen the full version of articles collected. The authors then gathered together and discussed about highly relevant studies that would be included in this review. Appraisal of study quality was performed by each authors independently and discussion was held if there was any disagreement about the selection and appraisal of the studies. The inherent aspects of the studies that consist of quality of the study, variables of relevant data, and also bias risk assessment were inde-pendently appraised by all authors by using forms filled by themselves. The first author then collected the forms and the contents of the form were evaluated to find any possible disagreements. The authors then had a meeting again to talk about any contradictions found and to find the decision according the appraisal of the studies.

Study Selection 

A total of 15 non-duplicate citations were found. 14 articles remained after a title and abstract screen. Full texts were screened using the pre-determined exclusion and inclusion criteria. Ten studies has to be excluded from the review because they do not have any out-comes of interest. Four articles were selected for this systematic review.

Study Characteristics 

There were 72 patients in total were included in this review. 62 patients underwent operative management while 10 patients had non-operative management. There were a total of 4 cohort prospective studies. Most studies classified their preoperative neurological status based on American Spinal Injury Association (ASIA) assessment protocol. The ASIA assessment protocol consists of a motor examination, two sensory examinations, and a framework of classification or impairment scale to quantify the severity of SCI.  26 from total patients have ASIA A preoperative neuro-logical status. Most SCI occurred on Thoracolumbal region as much as 62 patients. Operative management included stem cells administration that sourced from iliac crest, umbilical cord tissue, and mesenchymal stromal cells. All of the stem cells injected at spinal cord lesion included intratechal and subarachnoid administration. All the patients have improvement after stem cells administration based on ASIA (Ame-rican Spinal Injury Association) assessment. There is adverse event reactions from the stem cells admin-istration such as mentioned on Vaquero et al. (2017) (84.21%) were considered mild headache, 3 (15.79%) moderate headache. 

Table 2: Study Characteristic.  

But from Mendonça, et al study, none of the subjects had fever, infection or meningitis after intervention. Follow up period varies from 3 months to 12 months.

This systematic review included 4 studies which eva-luated the outcome of stem cell transplantations com-prehensively for management of SCI patients. Al-though the effectiveness of stem cell transplantation for the management of SCI patients remains debatable and unclear, this study found that stem cell transp-lantation significantly improved the neurological fun-ctions and outcomes (reflected by the ASIA and VAS) if compared to rehabilitation therapy. This systematic review only found cohort prospective study. There was no RCT study regarding the outcome of SC transplant-ation for SCI patients. This finding might be happen because this treatment of SC transplantation is rela-tively new treatment for SCI patients (Muheremu et al., 2016). 

Table 3: Summary of total sample, demographic data, spinal level and preoperative spinal status.

Most studies classified their preoperative neurological status based on ASIA assessment protocol including two sensory examinations, a motor examination and a classification framework or impairment scale. There were 26 from total 72 patients had ASIA A preopera-tive neurological status. All the patients had improve-ment after stem cells administration based on ASIA assessment. Most spinal cord injury occurred on tho-racolumbal region as much as 62 patients. This might occur because of thoracolumbar region is the most frequent site of SCI patients (Cho et al., 2009). Al-though there were some adverse effects according to the results of this study.  

Table 4: Stem cell transplantation surgery technique.

The all of them were only mild and temporary side effects, including fever, headache, urinary tract in-fections, nausea, numbness, backache, and abdominal distension, which mainly due to spinal puncture. There were no puncture wound infection, intracranial in-fection, leakage of cerebrospinal fluid from the in-cision, or any other severe or long term adverse effects observed in the subjects, indicating that stem cell transplantation is a considerably safe modality. 

Table 5: Outcome of stem cell transplantation.

There were some limitations exist in this study. First, this review only included 4 studies due to the limit-ation of literatures, so there were some important sub-group analyses that was not be able to be performed such as the diseases different courses and number of cells transplanted to the subjects. The second limitation is that only papers published in English were included in this systematic review, so there may be another eligible studies in language other than English that relevant and can be included in this review. Review which included multi-centric randomized control trials with large size of randomizes subjects, reasonable generation of random sequence, adequate allocation concealment, and low risk of reporting bias will be needed to find evidence base with higher quality.

Stem cells transplantation yielded satisfactory result in comparison to conventional management of SCI pati-ents, in which all the patients was found to have imp-rovement after stem cells administration based on ASIA assessment. Many neuroprotective factors and cytokines, including BDNF, GDNF, and VEGF that were secreted by MSCs thought to be the reason in its superiority in differentiation and replacement for the damaged cells. Some adverse effects were observed, including fever, headache, urinary tract infections, nausea, numbness, backache, and abdominal disten-sion, which mainly due to spinal puncture, and were found to be only mild and temporary. There was no puncture wound infection, leakage of cerebrospinal fluid from the incision, intracranial infection, or any other severe or long term adverse effects observed in the subjects, indicating that stem cell transplantation is a considerably safe modality. Future prospective studies with longer observation periods should be per-formed to cement the validity of this finding.

The current review was conducted through collabora-tions from all the authors. Thanks to all the thank all of the people who helped with the research.

All authors declare that they have no competing interests. No funding was received for this study