Spinal cord injury (SCI) is a devastating disorder, affecting 2.5 million people across the world, with more than 130,000 new injuries added each year.1 Presently, there is no cure or effective standard of care for SCI. Many treatments have been tested in clinical trials, including the use of methylprednisolone,2,3 GM1 ganglioside,4 decompression,5 and 4-aminopyridine,6 all of which have produced only marginal benefits with adverse side effects. The present standard of care for SCI is decompression of the injured cord and fixation of the spine. However, this treatment has not prevented the pathological cascade triggered by SCI.
Therefore, the quest for functional recovery exemplifies a need for cellular replacement strategies.7–9 However, the heterogeneity of human SCI represents an enormous challenge for finding a standard of care. With stem cell technology, there is potential of partial functional recovery, leading to an improved quality of life.10,11
In SCI, a large proportion of neurons at the injury site die, and it is believed that replacing these dead neuronal cells with stem cells within the spinal cord can improve reconnection to the neurons. Stem cells may be used to replace the nerve cells that have died as a result of the injury, generate new supporting cells that will reform the insulating nerve sheath (myelin), and stimulate regrowth of damaged nerves. When introduced into the spinal cord shortly after injury, stem cells may protect the cells at the injury site from further damage, by releasing protective factors. Many sources are being utilized for stem cells; however, bone marrow–derived mesenchymal stem cells (BM-MSCs) have added advantages in ethical and immunological concerns.
BM-MSCs can be transplanted via intravenous, intrathecal, and direct intramedullary routes. Studies conducted so far have mentioned the utility of intravenous and intrathecal routes as the most frequent; however, the intramedullary direct route has not been implicated to that extent. Some studies reported to date have assessed the outcome in subacute or chronic SCI.12–14 We therefore aimed to estimate the safety and feasibility of intramedullary injected bone marrow–derived stem cells in acute complete SCI.
Methods
Patients presenting with a complete SCI (quadriplegia or paraplegia) requiring surgical intervention within 1 week of injury were enrolled if they fulfilled the following inclusion criteria: age between 18 and 50 years and traumatic complete SCI (American Spinal Injury Association grade A). Patients were excluded if there was anatomical transection of the cord visualized on MRI. Patients with severe fracture dislocations, history of myocardial infarction or coronary artery disease, chronic infections, HIV or HBsAg (hepatitis B surface antigen), history of liver or renal insufficiency or of any malignancy, inability to communicate effectively with the neurological examiner, and active participation in another experimental procedure/intervention, as well as pregnant or nursing women, were not included. Approval from the institution’s ethics committee and stem cell committee was obtained for this study.
Randomization
Random numbers were generated using a computer program and were achieved using permuted blocks of variable length. Sequentially numbered opaque sealed envelopes enclosing assignments were kept at the clinical research facility.
Patients were randomized immediately after ascertaining the treatment status. Based on randomization, patients were divided into two groups: the stem cell group, dural incision (intramedullary) stem cell infusion plus standard therapy; and the placebo group, standard therapy in the hospital plus dural incision with injection of placebo (plasma).
Allocation Concealment
Sealed envelopes with the assigned intervention corresponding to the random code were kept with the chief guide. Patients who fulfilled eligibility criteria were included in the study. Both the patient and neurosurgeon were unaware of the allocation of the treatment after randomization.
Stem Cell Processing
Bone marrow aspiration (100 ml) was done from the iliac crest using aseptic precautions at the same time when iliac graft was taken for spinal cord decompression and stabilization. Bone marrow was collected in the standard blood collection bag with acid citrate dextrose/citrate phosphate dextrose adenine with or without preservative free heparin. Systemic heparin was administered at 25 IU/kg prior to the bone marrow harvest. This procedure was performed under the supervision of an anesthetist. Mononuclear BM-MSCs were separated under good laboratory practice conditions by SmartPReP2 System bone marrow aspirate concentrate (Harvest Technologies GmbH) in the sterile zone in the operating room. The device is a tabletop centrifuge system with disposable cuvettes consisting of two chambers. The first chamber contains a floating shelf of a specific density. During the initial centrifugation phase, the heavy red blood cells are separated from the nucleated cells and plasma. The cellular elements and plasma are automatically decanted into the second chamber and concentrated by centrifugation. A portion of the supernatant plasma is removed, and the cellular elements are resuspended in the remaining plasma.
The harvested mononuclear BM-MSCs were evaluated for their viability by the trypan blue dye exclusion test. Flow cytometry was done for CD34+ and CD105 counts (FACSCaliber, BD), and their morphology was assessed by Giemsa staining. For sterility, samples were sent for microbiology culture.
Operation and Introduction of Stem Cells
Patients initially underwent spinal cord decompression and stabilization. The dura mater was incised, sparing the arachnoid, which was subsequently opened separately with microscissors. The ventral surface of the contusion site (for cervical SCI) and the dorsal surface (for thoracolumbar SCI) were located using high-power microscopic magnification. After exposure of sufficient surface at the contusion site, 300-µl aliquots of cells (total volume of 1.8 ml) were injected into 6 separate positions surrounding the lesion site with the injection depth of 5 mm from the ventral surface and 5 mm lateral from the midline. To avoid mechanical injury during injection, 2 × 108 cells were injected at a rate of 300 µl/min using a 21-gauge needle attached to a 1-ml syringe by the operating surgeon. To prevent cell leakage through the injection track, the injection needle was left in position for 5 minutes after completing the injection. The dura mater and arachnoid were then closed with glue. The muscle and skin were closed in layers.
Observation After Intervention
Patients were monitored by the neurosurgery and research staff in the intensive care setting for 24 hours postprocedure and the following parameters were assessed: breathing difficulty, edema, inflammation, blood pressure, heart rate and arrhythmias on a cardiac monitor, headache, fever, chills and/or rigors, urticaria, and neuropathic pain. The patients were brought to the ward after stabilization and monitored by the research or neurosurgery staff.
Laboratory Parameters
Blood samples were obtained from each patient 12, 24, and 48 hours after stem cell injection for assessing renal (urea, creatinine, and uric acid), hepatic (alanine transaminase and aspartate transaminase), and hematological (white blood cell, platelet, and international normalized ratio) abnormalities.
Follow-Up
Patients were evaluated preoperatively and followed up at 3 and 6 months by MRI of the affected area of the spinal cord for evaluating the safety of the intramedullary route.
Statistical Analysis
Following the data collection in Microsoft Excel, data were analyzed statistically using SPSS software (version 13.0, SPSS Inc.). The Student t-test and chi-square test were used wherever necessary; p ≤ 0.05 was considered statistically significant.
Results
A total of 180 patients with complete SCI were screened from June 2013 to November 2014. Most of the patients screened had to be excluded due to delay in presentation after the injury. As the initial inclusion criteria allowed enrollment of patients within 72 hours of injury, the criteria were modified to include patients within 1 week of injury. Subsequently, 27 patients were enrolled during the study period (Fig. 1).
CONSORT trial flow diagram. Flow of study participants at different stages of the randomized controlled trial assessing the efficacy and outcome of BM-MSCs transplanted via the intramedullary route in acute SCI. Figure is available in color online only.
After randomization, there were 14 patients in the stem cell group and 13 patients in the placebo group. In the stem cell group, there were 12 males and 2 females with a male/female ratio of 5.5:1. In the control group, there were 11 males and 2 females with a male/female ratio of 6:1. The mean age in the stem cell group was 28.1 ± 18 years (range 18–50 years), and that in the control group was 32.6 ± 11.6 years (range 18–50 years). The mean weight in the stem cell group was 59.2 ± 7.6 kg (range 47–78 kg), and that in the control group was 62.4 ± 9.5 kg (range 48–80 kg). Both groups were well matched in terms of sex, age, and weight.
Type of Injury
There were 14 patients with complete paraplegia and none with quadriplegia in the stem cell group. In the control group, there were 11 patients with complete paraplegia and 2 patients with quadriplegia.
Mode of Injury
In the stem cell group, there were 6 patients with a history of fall, 5 with a history of road traffic accident, and 3 with other histories of a gunshot, assault, and electric shock. In the control group, there were 4 patients with a history of fall, 7 with a history of road traffic accident, none with gunshot injuries, and 2 patients with other histories (one patient was assaulted and the other was hit by a bull).
The variables and the respective number of patients in the control group and stem cell group are listed in Table 1. Laboratory values for renal (Table 2), hepatic (Table 3), hematological (Table 4), hemodynamic (Table 5), and clinical (Table 6) parameters remained normal at all time points in all patients.
Variables and respective patient number in control and stem cell groups
| Variable | Control Group | Stem Cell Group |
|---|---|---|
| No. of patients | 13 | 14 |
| Age, yrs | 32.6 ± 11.6 | 28.1 ± 18 |
| Weight, kg | 62.4 ± 9.5 | 59.2 ± 7.6 |
| Sex | ||
| Male | 11 | 12 |
| Female | 2 | 2 |
| Type of injury | ||
| Complete quadriplegia | 2 | 0 |
| Complete paraplegia | 11 | 14 |
| Level of injury | ||
| Cervical | 9 | 6 |
| Thoracic | 4 | 7 |
| Lumbar | 0 | 1 |
| Mode of injury | ||
| Fall | 4 | 6 |
| Road traffic accident | 7 | 5 |
| Gunshot | 0 | 1 |
| Assault | 1 | 1 |
| Electric shock | 0 | 1 |
| Hit by a bull | 1 | 0 |
Renal parameters
| Variable | Control Group (n = 11) | Stem Cell Group (n = 13) | p Value |
|---|---|---|---|
| Urea, mg/dL | |||
| Day 0 | 29.0 ± 13.6 | 32.2 ± 13.8 | 0.58 |
| Day 1 | 28.9 ± 13.5 | 30.6 ± 11.9 | 0.73 |
| Day 2 | 29.4 ± 8.8 | 31.4 ± 8.3 | 0.57 |
| Day 3 | 28.5 ± 8.9 | 30.3 ± 7.7 | 0.61 |
| Creatinine, mg/dL | |||
| Day 0 | 0.50 ± 0.16 | 0.56 ± 0.18 | 0.47 |
| Day 1 | 0.50 ± 0.23 | 0.58 ± 0.20 | 0.40 |
| Day 2 | 0.37 ± 0.10 | 0.44 ± 0.17 | 0.22 |
| Day 3 | 0.53 ± 0.09 | 0.51 ± 0.14 | 0.67 |
| Uric acid, mg/dL | |||
| Day 0 | 3.9 ± 0.76 | 3.4 ± 0.85 | 0.16 |
| Day 1 | 3.9 ± 0.89 | 3.2 ± 0.95 | 0.09 |
| Day 2 | 3.9 ± 0.80 | 3.3 ± 0.88 | 0.10 |
| Day 3 | 3.9 ± 0.70 | 3.3 ± 0.73 | 0.07 |
Hepatic parameters
| Variable | Control Group (n = 11) | Stem Cell Group (n = 13) | p Value |
|---|---|---|---|
| AST | |||
| Day 0 | 39.7 ± 5.4 | 39.7 ± 7.3 | 0.98 |
| Day 1 | 41.8 ± 6.8 | 39.7 ± 8.1 | 0.51 |
| Day 2 | 43.8 ± 7.5 | 40.4 ± 8.7 | 0.33 |
| Day 3 | 43.7 ± 5.3 | 41.3 ± 8.3 | 0.41 |
| ALT | |||
| Day 0 | 29.8 ± 9.4 | 28 ± 11.5 | 0.68 |
| Day 1 | 31.5 ± 8.0 | 28.3 ± 10.3 | 0.40 |
| Day 2 | 30.09 ± 8.8 | 28.6 ± 10.0 | 0.70 |
| Day 3 | 31.6 ± 8.2 | 28.6 ± 10.5 | 0.45 |
ALT = alanine transaminase; AST = aspartate transaminase.
Hematological parameters
| Variable | Control Group (n = 11) | Stem Cell Group (n = 13) | p Value |
|---|---|---|---|
| WBCs/mm3 | |||
| Day 0 | 13,800 ± 3722 | 12,393.85 ± 2378 | 0.27 |
| Day 1 | 13,936.36 ± 3280.3 | 12,513.85 ± 2620.8 | 0.25 |
| Day 2 | 13,463.64 ± 3243.5 | 13,030.77 ± 2384.1 | 0.71 |
| Day 3 | 12,500 ± 4692.7 | 13,001.54 ± 1800.2 | 0.72 |
| Platelets/mm3 | |||
| Day 0 | 206.09 ± 76.1 | 241.53 ± 95.4 | 0.33 |
| Day 1 | 205.45 ± 74.15 | 240.69 ± 89.4 | 0.31 |
| Day 2 | 211.27 ± 78.9 | 240.38 ± 92.9 | 0.42 |
| Day 3 | 208.09 ± 77.9 | 245.38 ± 89.2 | 0.29 |
| INR | |||
| Day 0 | 1.09 ± 0.11 | 1.10 ± 0.09 | 0.83 |
| Day 1 | 1.12 ± 0.13 | 1.10 ± 0.10 | 0.70 |
| Day 2 | 1.12 ± 0.10 | 1.08 ± 0.07 | 0.32 |
| Day 3 | 1.12 ± 0.09 | 1.09 ± 0.09 | 0.46 |
INR = international normalized ratio; WBC = white blood cell.
Hemodynamic parameters
| Variable | Control Group (n = 11) | Stem Cell Group (n = 14) | p Value |
|---|---|---|---|
| Temperature, °F | |||
| After 12 hrs | 98.6 ± 0.44 | 98.5 ± 0.13 | 0.42 |
| After 24 hrs | 99.1 ± 0.81 | 98.6 ± 0.42 | 0.05 |
| After 48 hrs | 98.6 ± 0.41 | 98.6 ± 0.44 | 0.97 |
| Systolic blood pressure, mm Hg | |||
| After 12 hrs | 124.7 ± 12.3 | 116.4 ± 12.6 | 0.49 |
| After 24 hrs | 120.3 ± 6.1 | 116.1 ± 11.8 | 0.29 |
| After 48 hrs | 118.4 ± 11.0 | 117.0 ± 9.1 | 0.73 |
| Diastolic blood pressure, mm Hg | |||
| After 12 hrs | 72.0 ± 8.58 | 75.0 ± 9.48 | 0.42 |
| After 24 hrs | 72.5 ± 9.83 | 69.2 ± 13.3 | 0.50 |
| After 48 hrs | 73.2 ± 9.89 | 67.2 ± 10.90 | 0.16 |
| Heart rate, bpm | |||
| After 12 hrs | 72.4 ± 14.25 | 79.3 ± 15.04 | 0.25 |
| After 24 hrs | 68.6 ± 12.73 | 85.1 ± 16.56 | 0.05 |
| After 48 hrs | 80.6 ± 23.13 | 88.4 ± 19.01 | 0.36 |
Other clinical parameters
| Variable | Control, n (%) | Stem Cell Group, n (%) | p Value |
|---|---|---|---|
| Breathing difficulty | |||
| After 12 hrs | 0.68 | ||
| No | 7 (63.6) | 11 (78.6) | |
| Yes | 4 (36.4) | 3 (21.4) | |
| After 24 hrs | 0.68 | ||
| No | 7 (63.6) | 11 (78.6) | |
| Yes | 4 (36.4) | 3 (21.4) | |
| After 48 hrs | 0.68 | ||
| No | 7 (63.6) | 11 (78.6) | |
| Yes | 4 (36.4) | 3 (21.4) | |
| Bradycardia | |||
| After 12 hrs | 0.565 | ||
| No | 9 (81.8) | 13 (92.9) | |
| Yes | 2 (18.2) | 1 (7.14) | |
| After 24 hrs | 0.07 | ||
| No | 8 (72.7) | 14 (100) | |
| Yes | 3 (27.3) | 0 | |
| After 48 hrs | 0.183 | ||
| No | 9 (81.8) | 14 (100) | |
| Yes | 2 (18.1) | 0 | |
| Tachycardia | |||
| After 12 hrs | >0.99 | ||
| No | 11 (100) | 13 (92.9) | |
| Yes | 0 | 1 (7.14) | |
| After 24 hrs | 0.23 | ||
| Yes | 11 (100) | 11 (78.6) | |
| No | 0 | 3 (21.4) | |
| After 48 hrs | >0.99 | ||
| Yes | 9 (81.8) | 11 (78.6) | |
| No | 2 (18.1) | 3 (21.4) |
No changes seen in O2 saturation, chills, rigor, or urticaria in either group.
In the stem cell group, all patients underwent preoperative MRI of the spinal cord at the affected level (Table 7). Follow-up MRI was available in 4 patients (29%) after 3 months and only 2 patients after 6 months. There was a decrease in the diameter of the cord progressively in all patients. In patients with follow-up MRI data available, cystic degeneration persisted in all patients at 3 months’ follow-up but disappeared by 6 months. Syringomyelia and cord edema persisted in 2 patients at the 3-month follow-up but disappeared by 6 months.
MRI findings of the two groups
| Change in Spinal Cord | Control Group (n = 6) | Stem Cell Group (n = 4) | ||||
|---|---|---|---|---|---|---|
| Baseline | 3 Mos (n = 6) | 6 Mos (n = 2) | Baseline | 3 Mos (n = 4) | 6 Mos (n = 2) | |
| Diameter | ||||||
| Increase diameter | ||||||
| No change | 1 | 1 | ||||
| Decrease diameter | 6 | 1 | 4 | 1 | ||
| Cord atrophy distal to the lesion | Absent | Absent | Absent | Absent | Absent | Absent |
| Enhancement | Absent | Absent | Absent | Absent | Absent | Absent |
| Cord edema | Absent | Absent | Absent | 2 | 2 | Absent |
| Cystic change | 1 | 1 | 1 | 4 | 4 | Absent |
| Syringomyelia | 2 | 2 | 1 | 2 | 2 | Absent |
In the placebo group, MRI was available at 3 months in 6 patients (46%) and showed a decrease in cord diameter in all. There was no cord enhancement, cord edema, or distal cord atrophy in any of the patients. One patient had persistent cystic degeneration at 6 months (similar to baseline MRI findings).
Radiographic evidence for one patient in the control group and another in the stem cell group at baseline and 3 months and 6 months of follow-up is shown in Fig. 2.
Sagittal MR images obtained in one patient in the control group (upper) and another patient in the stem cell group (lower) at baseline, 3 months, and 6 months. In the control group, there was a decrease in cord diameter at 3 months while there was no cord enhancement, cord edema, or distal cord atrophy at 6 months. In the stem cell group, cystic degeneration persisted at the 3-month follow-up but disappeared by 6 months.
Mortality
Five patients in the placebo group and 3 patients in the stem cell group died during the follow-up period. This difference was not statistically significant (p = 0.31). All patients who died had high cervical SCIs, and the cause of death was ventilator-associated pneumonitis.
Oncological Outcome
No tumors were found on MRI investigation at a follow-up of 6 months in any of the patients.
Discussion
To the best of our knowledge, this is the first study to assess the safety and feasibility of intramedullary transplanted BM-MSCs as a potential therapy for patients with acute complete SCI. Therapeutic advantages of stem cells in SCI include bridging any cysts or cavities, replacing the dead cells by providing new neurons or myelinating cells, and creating a favorable environment for axon regeneration. BM-MSCs have shown promising results as a therapy for acute and chronic SCI in experimental animal cases,15 and several preliminary attempts have been made to extrapolate them in human clinical trials, with much emphasis on safety.15–20 Clinical trials using autologous BM-MSCs in spinal cord–related ailments or injuries such as amyotrophic lateral sclerosis, multiple sclerosis, and traumatic SCI are being conducted elsewhere, with limited sample size.21–23 Except for minor tingling sensations in our study, no allergic or inflammatory reactions or any major adverse reactions so far have been reported with the use of autologous BM-MSCs for SCI. BM-MSCs are associated with the least immunological rejection in comparison with stem cells of other origin.24 Additionally, they have minimal ethics concerns.24 Hence, BM-MSCs are gaining momentum as a therapeutic agent for SCI.
Intravascular transplantation25–27 and delivery into CSF are the less-invasive methods for stem cell injection. Direct injection into the site of injury has been implicated as the most common method of delivery in animal models.28–30 However, due to further risk of injury to the spinal cord, direct injection might be inappropriate in humans despite delivery of the desired number of cells. In animals, intrathecal delivery via lumbar puncture has been reported to be safer and more effective than direct injection.31
Unlike acute SCI, the wound healing process and homing effect (i.e., the process by which stem cells can migrate to the pathologic sites) disappears in chronic SCI.32–34 Therefore, we believe that direct injection of BM-MSCs into the spinal cord is most effective for delivering BM-MSCs to the optimal site, which is a chronic lesion without a homing effect. Direct intramedullary injection of BM-MSCs in SCI patients did not result in permanent complications, such as infection, tumor formation, syrinx formation, ectopic calcification, or aggravated chronic pain, including allodynia or paresthesia.
Although there are studies in which BM-MSCs have been injected intramedullary into the spinal cord in SCI in humans, these studies have reported on patients with chronic injury; there are very few trials available for acute SCI.14,35 Moreover, there may be biological differences between stem cell studies done on Indians and non-Indians. It was therefore imperative that a study be done simultaneously to assess for the safety and feasibility of intramedullary injected BM-MSCs in acute complete SCI. As all patients require surgical decompression and stabilization of the spinal cord in the acute phase, intramedullary injection may be particularly suitable at this stage.
MRI of the affected region was performed for all patients at baseline, and they were followed up to monitor for radiological evidence of any deleterious effect of intramedullary injection. All patients for whom follow-up was available (control, n = 6; stem cell group, n = 4) showed a decrease in cord diameter on serial MRI. There was no cord enhancement, cord edema, or distal cord atrophy in any of the patients. One patient had persisting cystic degeneration at 6 months, which was similar to baseline MRI findings.
Toxicological data were recorded for each patient, and adverse events (if any) were recorded as well. No adverse events related to stem cell injection were noted for renal, hepatic, hematological, hemodynamic, and clinical parameters in this study. There was also no difference in mortality rate between the two groups in the study period.
The major limitations of this study were the slow accrual of patients and loss to follow-up. This could be due to the strict inclusion criteria and can be seen from the fact that, although we screened 180 patients in the study period, we could include only 27. Of these 27 patients, 3 patients withdrew, 3 patients were lost to follow-up, and 8 patients died, leaving 13 patients for final analysis. Nevertheless, we believe that the results are sound and will be replicated across larger studies.
Conclusions
Harvesting of BM-MSCs using a point-of-care kit was found to be technically feasible and provided CD34+ cells of high viability and purity. In addition, intramedullary injection of BM-MSCs was found to be safe and feasible for use in human SCI. Our study paves the way for larger human studies on intramedullary use of BM-MSCs in SCI.
Disclosures
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
Author Contributions
Conception and design: Agrawal, Saini. Acquisition of data: Saini. Analysis and interpretation of data: Pahwa. Drafting the article: Saini, Pahwa. Critically revising the article: Pahwa. Reviewed submitted version of manuscript: Agrawal. Statistical analysis: Saini. Administrative/technical/material support: Agrawal. Study supervision: Singh, Gurjar, Mishra, Jagdevan, Misra.
References
- 1↑
World Health Organization. International perspectives on spinal cord injury. 2013.Accessed February 23, 2022. https://www.who.int/publications/i/item/international-perspectives-on-spinal-cord-injury
- 2↑
Bracken MB. Methylprednisolone in the management of acute spinal cord injuries. Med J Aust. 1990;153(6):368.
- 3↑
Bracken MB, Shepard MJ, Collins WF, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med. 1990;322(20):1405–1411.
- 4↑
Geisler FH, Coleman WP, Grieco G, Poonian D. The Sygen multicenter acute spinal cord injury study. Spine (Phila Pa 1976). 2001;26(24 Suppl):S87–S98.
- 5↑
Vaccaro AR, Daugherty RJ, Sheehan TP, et al. Neurologic outcome of early versus late surgery for cervical spinal cord injury. Spine (Phila Pa 1976). 1997;22(22):2609–2613.
- 6↑
Cardenas DD, Ditunno J, Graziani V, et al. Phase 2 trial of sustained-release fampridine in chronic spinal cord injury. Spinal Cord. 2007;45(2):158–168.
- 7↑
Garbossa D, Fontanella M, Fronda C, et al. New strategies for repairing the injured spinal cord: the role of stem cells. Neurol Res. 2006;28(5):500–504.
- 8↑
Keirstead HS, Nistor G, Bernal G, et al. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci. 2005;25(19):4694–4705.
- 9↑
Popa ER, Harmsen MC, Tio RA, et al. Circulating CD34+ progenitor cells modulate host angiogenesis and inflammation in vivo. J Mol Cell Cardiol. 2006;41(1):86–96.
- 10↑
Anderson KD. Targeting recovery: priorities of the spinal cord-injured population. J Neurotrauma. 2004;21(10):1371–1383.
- 11↑
Lima C, Escada P, Pratas-Vital J, et al. Olfactory mucosal autografts and rehabilitation for chronic traumatic spinal cord injury. Neurorehabil Neural Repair. 2010;24(1):10–22.
- 12↑
Saberi H, Firouzi M, Habibi Z, et al. Safety of intramedullary Schwann cell transplantation for postrehabilitation spinal cord injuries: 2-year follow-up of 33 cases. J Neurosurg Spine. 2011;15(5):515–525.
- 13
Jeon SR, Park JH, Lee JH, et al. Treatment of spinal cord injury with bone marrow-derived, cultured autologous mesenchymal stem cells. Tissue Eng Regen Med. 2010;7(3):316–322.
- 14↑
Park JH, Kim DY, Sung IY, et al. Long-term results of spinal cord injury therapy using mesenchymal stem cells derived from bone marrow in humans. Neurosurgery. 2012;70(5):1238–1247.
- 15↑
Deng YB, Liu XG, Liu ZG, Liu XL, Liu Y, Zhou GQ. Implantation of BM mesenchymal stem cells into injured spinal cord elicits de novo neurogenesis and functional recovery: evidence from a study in rhesus monkeys. Cytotherapy. 2006;8(3):210–214.
- 16
Syková E, Homola A, Mazanec R, et al. Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant. 2006;15(8-9):675–687.
- 17
Geffner LF, Santacruz P, Izurieta M, et al. Administration of autologous bone marrow stem cells into spinal cord injury patients via multiple routes is safe and improves their quality of life: comprehensive case studies. Cell Transplant. 2008;17(12):1277–1293.
- 18
Park HC, Shim YS, Ha Y, et al. Treatment of complete spinal cord injury patients by autologous bone marrow cell transplantation and administration of granulocyte-macrophage colony stimulating factor. Tissue Eng. 2005;11(5-6):913–922.
- 19
Yoon SH, Shim YS, Park YH, et al. Complete spinal cord injury treatment using autologous bone marrow cell transplantation and bone marrow stimulation with granulocyte macrophage-colony stimulating factor: phase I/II clinical trial. Stem Cells. 2007;25(8):2066–2073.
- 20↑
Kumar AA, Kumar SR, Narayanan R, Arul K, Baskaran M. Autologous bone marrow derived mononuclear cell therapy for spinal cord injury: a phase I/II clinical safety and primary efficacy data. Exp Clin Transplant. 2009;7(4):241–248.
- 21↑
Samijn JP, te Boekhorst PA, Mondria T, et al. Intense T cell depletion followed by autologous bone marrow transplantation for severe multiple sclerosis. J Neurol Neurosurg Psychiatry. 2006;77(1):46–50.
- 22
Cristante AF, Barros-Filho TE, Tatsui N, et al. Stem cells in the treatment of chronic spinal cord injury: evaluation of somatosensitive evoked potentials in 39 patients. Spinal Cord. 2009;47(10):733–738.
- 23↑
Deda H, Inci MC, Kürekçi AE, et al. Treatment of amyotrophic lateral sclerosis patients by autologous bone marrow-derived hematopoietic stem cell transplantation: a 1-year follow-up. Cytotherapy. 2009;11(1):18–25.
- 24↑
Akiyama Y, Radtke C, Kocsis JD. Remyelination of the rat spinal cord by transplantation of identified bone marrow stromal cells. J Neurosci. 2002;22(15):6623–6630.
- 25↑
Takeuchi H, Natsume A, Wakabayashi T, et al. Intravenously transplanted human neural stem cells migrate to the injured spinal cord in adult mice in an SDF-1- and HGF-dependent manner. Neurosci Lett. 2007;426(2):69–74.
- 26
Urdzíková L, Jendelová P, Glogarová K, Burian M, Hájek M, Syková E. Transplantation of bone marrow stem cells as well as mobilization by granulocyte-colony stimulating factor promotes recovery after spinal cord injury in rats. J Neurotrauma. 2006;23(9):1379–1391.
- 27↑
Vaquero J, Zurita M, Oya S, Santos M. Cell therapy using bone marrow stromal cells in chronic paraplegic rats: systemic or local administration?. Neurosci Lett. 2006;398(1-2):129–134.
- 28↑
Himes BT, Neuhuber B, Coleman C, et al. Recovery of function following grafting of human bone marrow-derived stromal cells into the injured spinal cord. Neurorehabil Neural Repair. 2006;20(2):278–296.
- 29
Karimi-Abdolrezaee S, Eftekharpour E, Wang J, Morshead CM, Fehlings MG. Delayed transplantation of adult neural precursor cells promotes remyelination and functional neurological recovery after spinal cord injury. J Neurosci. 2006;26(13):3377–3389.
- 30↑
Parr AM, Kulbatski I, Tator CH. Transplantation of adult rat spinal cord stem/progenitor cells for spinal cord injury. J Neurotrauma. 2007;24(5):835–845.
- 31↑
Pal R, Gopinath C, Rao NM, et al. Functional recovery after transplantation of bone marrow-derived human mesenchymal stromal cells in a rat model of spinal cord injury. Cytotherapy. 2010;12(6):792–806.
- 32↑
Yagi H, Soto-Gutierrez A, Parekkadan B, et al. Mesenchymal stem cells: mechanisms of immunomodulation and homing. Cell Transplant. 2010;19(6):667–679.
- 33
Zieker D, Schäfer R, Glatzle J, et al. Lactate modulates gene expression in human mesenchymal stem cells. Langenbecks Arch Surg. 2008;393(3):297–301.
- 34↑
McColgan P, Sharma P, Bentley P. Stem cell tracking in human trials: a meta-regression. Stem Cell Rev Rep. 2011;7(4):1031–1040.
- 35↑
Pal R, Venkataramana NK, Bansal A, et al. Ex vivo-expanded autologous bone marrow-derived mesenchymal stromal cells in human spinal cord injury/paraplegia: a pilot clinical study. Cytotherapy. 2009;11(7):897–911.
