Current status and future perspectives on stem cell transplantation for spinal cord injury

Table 2 Summary of the studies included in the systematic literature review focusing on bone marrow derived stem cells (i.e., BMSC)

Ref.	Phase of clinical trial	Patients (n)	Localization of injury	Pre-treatment AIS classification or level of injury	Stem cells		Treatment			Follow up (months)	Outcomes
					Origin	Type	Dose	Administration route	Time from Injury		Functional improvement	Adverse effects
Park et al[37], 2005	N/A	6	Cervical	AIS A	Autologous (iliac bone marrow)	BMSC	1.98 × 1010	Intralesional	N/A	6-18	AIS A→C 4, AIS A→B: 1, AIS A=A: 1	No serious adverse effects
Sykova et al[11], 2006	N/A	20	Cervical and thoracic	AIS A: 15; AIS B: 4; AIS C: 1	Autologous (iliac bone marrow)	BMSC	104.0 ± 55.3 × 108	Intravenous + Intraarterial	Subacute or chronic	24	AIS A→B: 1, AIS B→D: 1, AIS=: 15	No serious adverse effects
Chernykh et al[12], 2007	N/A	18	Cervical, Thoracic, Lumbar	N/A	Autologous (iliac bone marrow)	BMSC	N/A	Intralesional+ Intravenous	Chronic	9.4 ± 4.6	ASIA scale: significant increase in total sensitivity and motor activity score	No serious adverse effects
Yoon et al[13], 2007	I/II	35	Cervical (4) and thoracic (4)	N/A	Autologous iliac bone marrow	BMSC	1 × 108	Intralesional	Intermediate	10.4	AIS grade increased in 30.4% of the acute and subacute treated patients (AIS A→B or A→C)	No serious adverse effects
Geffner et al[14], 2008	N/A	8	Thoracic	AIS A: 5, AIS B: 1, AIS C: 2	Autologous iliac bone marrow	BMSC	1.2 × 106/kg	Intrathecal	4 acute and 4 chronic (average 114 months)	24	AIS A→C: 4, AIS B→C: 1, AIS C→D: 1 AIS =: 2	No serious adverse effects
Adel et al[38], 2009	N/A	43	Cervical and thoracic	AIS A: 40, AIS C: 3	Autologous iliac bone marrow	BMSC	5-10 × 106	Intrathecal	Chronic (average 43.2 months)	6	AIS A→B: 11; AIS A→C: 1; AIS B→C: 3; AIS =: 28	ADEM: 1/43; Marked increased spasticity: 4/43; Neuropathic pain: 24/43
Kumar et al[39], 2009	I/II	297	N/A	AIS A: 249, AIS B: 12, AIS C: 34, AIS D: 2	Autologous iliac bone marrow	BMSC	N/A	Intrathecal	N/A	18.4-20.5	32.7% of the ASIA-classified patients showed improvement, in sensory and motor scale	No serious adverse effects. Mild-to-moderate neuropathic pain in few patients
Pal et al[40], 2009	N/A	30	Cervical and thoracic	AIS A: 24, AIS C: 6	Autologous iliac bone marrow	BMSC	1 × 106/kg	Intrathecal	< 6 months: 20, > 6 months: 30	12-36	No changes in the ASIA scale, SSEP, MEP and NCV	No serious adverse effects. Neuropathic pain in two patients
Abdelaziz et al[41], 2010	N/A	20	Thoracic	AIS A: 10, AIS B: 5, AIS C: 5	Autologous iliac bone marrow	BMSC	5 × 106/kg	Intrathecal + Intralesional	Chronic (> 6 months)	12	AIS A→B: 1, AIS A→C: 2, AIS B→C: 3; AIS=: 14	No serious adverse effects.Headache (12) and fever (3)
Bhanot et al[30], 2011	N/A	13	Cervical and thoracic	AIS A	Autologous	BMSC	3-6-8 × 106/kg	Intrathecal	Intermediate and chronic (3-132 months, average 28)	6-38	AIS A→B: 1, Patchy improvement in sensations below the injured level: 2, Patient subjectively felt improved sense of bladder filling: 1	No serious adverse effects. Transient increase in spasticity in the lower limbs (50%)
Park et al[35], 2012	N/A	10	Cervical	AIS A: 4, AIS B: 6	Autologous iliac bone marrow	BMSC	8 × 106 (intralesional) + 4 × 107 (subdural)	Intralesional + Subdural	> 1 months	6-62	Improvements in ADL, SSEP, MEP (3/10, all AIS B)	No serious adverse effects
Karamouzian et al[18], 2012	I/II	11	Thoracic	AIS A	Autologous iliac bone marrow	BMSC	0.7-1.2 × 106	Intrathecal	Acute and intermediate/chronic (max 1.5 months)	12-33	AIS A→C: 5, AIS=: 0	No serious adverse effects
Dai et al[28], 2013	N/A	20	Cervical	AIS A, ASIA score: 31.6 ± 9.82	Autologous iliac bone marrow	BMSC	2 × 107	Intralesional	Chronic (51.9 ± 18.3)	6	AIS A→B: 9, ASIA score: 43.1 ± 19.32	No serious adverse effects. Fever (2), Headache and dizziness (1), pain and numbness in spinal cord dominant area (2)
Jiang et al[19], 2013	N/A	20	Cervical (4), thoracic (11) and lumbar (5)	AIS A: 8, AIS B: 4, AIS C: 8	Autologous iliac bone marrow	BMSC	1 × 108	Intrathecal	Intermediate and chronic (3-120 months)	1	AIS A→B: 3, AIS A→C: 1, →AIS C→D: 8	No serious adverse effects. Fever and headache
Yazdani et al[42], 2013	I	8	Cervical (1) and thoracic (7)	AIS A	Autologous iliac bone marrow	BMSC	1 × 106	Intralesional	Chronic (13-63 months)	26-43	Although some improvement in light touch and pinprick sensation was observed, no improvement in ASIA classification was seen	No serious adverse effects
Amr et al[43], 2014	N/A	14	Thoracic	AIS A	Autologous iliac bone marrow	BMSC	N/A	Scaffold	Intermediate and chronic (5-84 months, average 23 months)	24	AIS A→B: 2, AIS A→C: 12	Haematoma formation (2), Seroma formation (2)
Suzuki et al[44], 2014	N/A	10	Cervical and thoracic	AIS A: 5, AIS B:5	Autologous iliac bone marrow	BMSC	2.03-8.44 × 108	Intrathecal	Intermediate and chronic (3 wk-12 months)	6	AIS A→B: 1, AIS B→C: 2, AIS B→D: 1; AIS=: 6	No serious adverse effects. Transient anemia after aspiration of bone-marrow cells (2)
Goni et al[45], 2014	N/A	9	Thoracic	AIS A	Autologous iliac bone marrow	BMSC	N/A	Intrathecal	Chronic	24	No significant difference in the ASIA score. Statistically significant differences in the Functional Independence Measure and Modified Ashworth Scale	No serious adverse effects. Postoperative temporary neuropathic pain (2)
El-kheir et al[10], 2014	I/II	50	Cervical (10) and thoracic (40)	AIS A: 15, AIS B: 35	Autologous iliac bone marrow	BMSC	2 × 106/kg	Intrathecal	Chronic (12-36 months, average 18.3 ± 5)	18	AIS A→B: 12, AIS A→C: 4, AIS B→C: 18; AIS=: 16	Temporary mild side effects: Headache, neuropathic pain (30%). No long-term side effects
Mendonca et al[46], 2014	I	14	Thoracic and lumbar	AIS A	Autologous iliac bone marrow	BMSC	5 × 106	Intralesional	Chronic (18-180 months)	6	AIS A→B: 6, AIS A→C: 1; AIS=: 5; Improvements in urologic function (9) and changes in SSEP (1)	One subject developed a postoperatory complication, evolving a cerebrospinal fluid leak that was treated by an additional surgical procedure
Shin et al[47], 2015	I/IIa	19	Cervical	AIS A: 17, AIS B: 2	Human fetal brain	NSC	1 × 108	Intralesional	Acute and intermediate	12	AIS A→C: 2, AIS A→B: 1, AIS B→D: 2; AIS=: 14. Positive response in SSEP (35.3%) and MEP (58.8%) activities of AIS-A patients below the level of injury	No serious adverse effects
Chhabra et al[48], 2016	I/II	7	Thoracic	AIS A, ISCIS total score: 162.6 ± 3.1	Autologous iliac bone marrow	BMSC	3.6 × 108	Intrathecal	Acute	12	ISCIS total score: 134.9 ± 2.5	Liver abscess (1)
Oraee-Yazdani et al[49], 2016	I	6	Cervical (1) and thoracic (5)	AIS A	Autologous iliac bone marrow	BMSC	2 × 106	Intrathecal	Chronic (38.1 ± 15.3 months average)	25-36	AIS A→B: 1. Improvement in sensory level (2), improvement in UDS, especially bladder compliance (1)	No serious adverse effects
Oh et al[32], 2016	III	16	Cervical	AIS B	Autologous iliac bone marrow	BMSC	4.8 × 107	Subdural	Chronic (24-181 months)	6	SEP improvement (4), MEP improvement (6), improvement in motor grade (2)	No serious adverse effects. 8 patients developed mild adverse effects (muscle rigidity, worsened symptoms of tingling sense)
Thakkar et al[33], 2016	N/A	10	Thoracic and lumbar	AIS A	Autologous bone marrow + abdominal adipose tissue	BMSC	1.82 × 108	Intrathecal	Chronic (30-64.8 months)	34	AIS A→B: 6, AIS A→C: 3, AIS A→D: 1	No serious adverse effects
Vaquero et al[27], 2016	I/II	12	Thoracic	AIS A, ASIA score: 165.92 ± 22.83	Autologous bone marrow	BMSC	100 × 106 - 230 × 106	Intralesional	Chronic (38.0-321 months, average 166.3)	12	AIS→B: 3, AIS A→C: 1, ASIA score: 213.25 ± 37.19	22 adverse events of minor (79.1%) or moderate (20.9%) intensity.
Kakabadze et al[25], 2016	I	18	Cervical and thoracic	AIS A: 10, AIS B: 5, AIS C: 3	Autologous iliac bone marrow	BMSC	405-964 × 106	Intrathecal	Intermediate and chronic (max 20 months)	12	ASIA scale improvement by one grade: 7/9 (78%) Improvement by two grades: 2/9 (22%)	No serious adverse effects. Transient fever and headache
Xiao et al[50], 2016	N/A	5	Cervical (1) and thoracic (4)	AIS A	Autologous iliac bone marrow	BMSC	1 × 109	Scaffold	Intermediate and chronic (max 32 months)	12	AIS A No improvement also in MEP and SSEP	No serious adverse effects.
Chhabra et al[51], 2017	I/II	7	Thoracic	AIS A, ISCIS total score: 172.2 ± 2.3	Autologous iliac bone marrow	BMSC	2 × 108	Intralesional	Acute	12	ISCIS total score: 141.7 ± 2.5	Liver abscess (1)
Vaquero et al[52], 2017	II	10	Cervical, thoracic and lumbar	AIS B: 5, AIS C: 5, ASIA total score: 118.2 ±60	Autologous	BMSC	30 × 106 × 4 doses	Intratechal	Chronic (29.2-415.1 months, mean 170.5 ± 118.6)	12	ASIA total score: 235.5 ± 49.35. Motor and sensory scores, bladder, bowel and sexual functions improved. Spasms (2) and neuropathic pain (2) improved	No serious adverse effects. Transient headache and pain in the area of the lumbar puncture
Larocca et al[21], 2017	I/II	5	Thoracic	AIS A	Autologous iliac bone marrow	BMSC	2 × 107	Subcutaneous	Chronic (25-111 months)	6	AIS A→B: 1, AIS A=: 5; One patient improved AIS A→B but reversed at 6 months. Improvements in SCIM III and FIM scale scores	No serious adverse effects
Vaquero et al[20], 2018	II	11	Cervical (4), thoracic (4) and lumbar (3)	AIS A: 3, AIS B: 4, AIS C: 3, AIS D: 1	Autologous	BMSC	100 × 106 × 3 doses	Intrathecal	Chronic (mean 163.8 ± 177.5 months)	10	AIS improvement in 27% of patients. AIS A→B: 1, AIS B→C: 1; AIS C→D: 1	No serious adverse effects. Transitory sciatic pain (37.5%), headaches and pain in the area of lumbar puncture
Guadalajara et al[53], 2018	Case report	1	Thoracic	AIS A	Autologous iliac bone marrow	BMSC	300 × 106 × 3 doses (1/months)	Intrathecal	Chronic	6	Improvement in functionality and especially in Krogh's; Neurogenic Bowel Dysfunction scale	No serious adverse effects
Srivastava et al[54], 2019	I	70	Thoracic and lumbar	AIS A	Autologous iliac bone marrow	BMSC	2,41 ± 1,198 × 106	Intrathecal	Acute and intermediate	12	AIS A→B: 21, AIS A→C: 29, AIS A→D: 5; AIS=: 15	No serious adverse effects
Phedy et al[55], 2019	Case report	1	Thoracic	AIS A	Autologous iliac bone marrow	BMSC	10 − 17 × 106 (× 7 times)	Intrathecal ×1 + Intravenous ×6	Chronic	60	AIS A→C. Increase in AIS score: 10→30. Increase in MRC score for L1 and L2 innervated muscles: 0/5→3/5	No serious adverse effects
Chen et al[56], 2020	I	7	Thoracic	AIS A	Autologous iliac bone marrow	BMSC	> 1 × 109	Scaffold	Acute or intermediate	36	All patients showed significant improvements in the FIM and ADL score. No obvious improvement in the ASIA grade, ASIA motor score, motor function, SSEPs, or MEPs was observed	Stress ulcer and lung infection (1), transient hyperthermia (1), shallow wound (1), spasm (4), paraplegic neuralgia (3), pressure ulcers (1), and lower limb amyotrophy (1)
Sharma et al[57], 2020	N/A	180	Cervical (63), thoracic and lumbar (117)	AIS A: 138, AIS B: 28, AIS C: 10, AIS D: 3	Autologous iliac bone marrow	BMSC	1.06 × 108	Intrathecal	Intermediate or chronic	2-16	FIM and WISCI showed statistically significant improvement	No serious adverse effects
Song et al[58], 2020	N/A	18	Cervical, thoracic and lumbar	ASIA score: 59.75 ± 5.22, SCIM-III score: 40.83 ± 6.58	Autologous iliac bone marrow	BMSC	1 × 107	Intrathecal	N/A	12	ASIA score: 81.1 ± 3.8, SCIM-III score: 72.5 ± 4.3	No serious adverse effects
Oraee-Yazdani et al[36], 2021	I/II	6	Cervical (1) and thoracic (5)	AIS A, SCIM III score: 28.9 ± 13	Autologous iliac bone marrow	BMSC	1 × 106	Intrathecal	Chronic (max 12 months)	30	SCIM III score: 43.1 ± 25.8. Sensory and/or motor improvement was evident in 9 patients according to the AIS assessment	Mild adverse effects: Increase in spasticity, numbness, or tingling sensation, and neuropathic pain
Honmou et al[59], 2021	II	13	Cervical	AIS A: 6, AIS B: 2, AIS C: 5	Autologous	BMSC (auto-serum expanded)	84−150 × 106	Intravenous	Subacute	6	AIS A→B (3/6 patients), A→C (2/6), B→C (1/2), B→D (1/2), C→D (5/5)	No serious adverse effects

Time from injury: Immediate: 0 - 2 h after the injury; acute: Early acute phase: 2 - 48 h; subacute: 2 d - 2 wk; intermediate: 2 wk - 6 months; chronic phase: > 6 months. AIS: American spinal injury association Impairment Scale; ASIA: American Spinal Injury Association; BMSC: Bone Marrow Mesenchymal Stromal Cells; N/A: Not available; NSC: Neural stem cells.