Review of operative considerations in spinal cord stem cell therapy

Table 1 Summary of clinical trials using stem cell therapy in spinal cord injury

Ref.	Patients	n	Technical description	Outcomes
Levi et al[17], 2019	Chronic C-SCI patients	12	Perilesional intramedullary injection of human CNS-SCs using a two-hand stabilization technique	UEMS showed an increase in treatment group compared to control untreated SCI patients (2.8 points in 9 mo)
Curtis et al[11], 2018	Chronic T-SCI	4	Instrumentation removal, laminectomy, durotomy and stereotactic injection-using a floating cannula of spinal cord-derived neural stem cells	ISNCSCI improvement in 2 subjects with no adverse events
Levi et al[8], 2018	Chronic C/T-SCI	29	Free-hand intramedullary injection of human CNS-SCs	13/29 patients experienced adverse events, all resolved by 3 mo
Xiao et al[12], 2018	Acute C/T-SCI	2	SCI injury site confirmed as complete and excised, collagen scaffold with hUC-MSCs transplanted as a bridge across injury site	Both patients improved from ASIA A → ASIA C
Vaquero et al[27], 2018	Chronic SCI patients	9	Three intrathecal injections of 100 × 106 MSCs	44% patients increased voluntary muscle contraction and 66% improved in bladder compliance with no adverse effects
Anderson et al[25], 2017	Subacute T-SCI	6	U/S + MRI used for navigation. Table mount (Geron Corp) and Hamilton syringe used for intramedullary microinjection of sural nerve-derived SCs	No major adverse events and no consistent improvement in ISNCSCI
Vaquero et al[18], 2017	Chronic incomplete C/T/L SCI	12	Subarachnoid administration via lumbar puncture of autologous MSCs	Sexual function (2/8), spasticity (3/9) and bowel/bladder function improved (8/9) improvements were noted
Vaquero et al[28], 2016	Chronic complete C/T/L SCI	12	Subarachnoid administration via lumbar puncture of autologous MSCs	All patients experienced improvement in sensation and sphincter control. Motor activity below the lesion obtained in 50% of patients
Satti et al[29], 2016	Chronic and subacute T-SCI	6	Intrathecal injection of autologous MSCs	Evaluated safety only-no adverse events
Bansal et al[22], 2016	SCI patients	8	Lumbar puncture at L1/L2 with autologous BMSCs injected 3 times every 4 wk	Patients with injury less than 6 mo improved-ASIA grade improvement in 6/10, walking with support restored in 8/10
Hur et al[21], 2016	Subacute to chronic C/T/L-SCI	14	Intrathecal injection through lumbar tap of 9 × 107 ADMSC	ASIA motor improved in ⅝ patients. 4 adverse events included headache and UTI
Oh et al[10], 2016	Chronic C-SCI	16	Laminectomy and durotomy with 1.6 × 107 BM-MSCs in 1 mL injected intramedullary with a 27 gauge needle. Fibrin glue used to prevent cell leakage. 3.2 × 107 BM-MSCs injected into the subdural space	12.5% of patients with significant motor improvement
Shin et al[20], 2015	Acute/subacute C- SCI	15	Human fetal tissue-derived neural stem cell progenitor cells free hand injection 5 mm deep into lesion site	5/19 in the treatment group with improved ASIA grade, compared to 1/15 in the control group with ASIA improvement
Mendonça et al[19], 2014	Chronic T/L-SCI	14	BM-MSCs injected based on lesion volume. Direct injection above and below level	8/14 developed lower limb functional gain in hip flexors. 7/14 improved ASIA grades to B/C 9/14 with improved urologic function
Cheng et al[30], 2014	Chronic T/L-SCI	10	CT-guided intramedullary injection at the lesion site using purified UC-MSCs. Two transplantations separated by 10 d, each transplantation with 3 separate injections of 2 × 107 cells	7/10 patients had significant improvement in movement and muscle tension
Al-Zoubi et al[31], 2014	Chronic T-SCI	19	Autologous purified CD34+/CD133+ SCs injected into cyst cavity or subarachnoid space	7/19 patients with segmental sensory improvement, 2/19 with motor improvement (ASIA-A → ASIA-C)
Yoon et al[23], 2014	Acute/subacute/chronic C-SCI	25	Intramedullary perilesional injection of 2 × 108 BMCs in 6 locations + 5 cycles of GM-CSF Subq	ASIA grade increased in 30.4% of acute and subacute treated patients with no improvement in chronic treatment group
Dai et al[32], 2013	Chronic complete C-SCI	20	BMMSC transplantation at site of injury with MIS-laminectomy, dural incision and injection at a depth of 3 mm at central dorsal aspect of the junction between the lesioned and normal spinal cord.	10/20 in BMMSC transplantation group had improvement in motor, light touch and pinprick sensory with 9/20 showing ASIA improvement. No improvement in any control patients (0/20)
Park et al[9], 2012	Traumatic C-SCI	10	Laminectomy and durotomy with 8 × 106 MSCs in 1 mL injected intramedullary over 10 s with a 26.5 gauge needle. Fibrin glue used to prevent cell leakage. At 4-8 wks post-op additional 5 × 107 MSCs injected via lumbar tap	6/10 patients with motor power improvement of UE
Frolov et al[33], 2012	Chronic C-SCI	20	Repeated intrathecal autologous HSCs (from leukapheresis) repeatedly injected over 1 yr	3-4 patients with improved SEP and MEP
Karamouzian et al[24], 2012	Acute/subacute T-SCI	11	Purified BM-MSC injected via standard lumbar puncture needle	5/11 in BM-MSC treatment group had two grade improvement in ASIA score (i.e. A → C) compared to 3/20 in control group (P = 0.09)
Ra et al[34], 2011	Chronic SCI	8	IV administration of human ADMSCs	Safe with no adverse events related to transplantation at 3 mo
Lima et al[14], 2009	Chronic C/T SCI	20	Laminectomy with partial scar excision and olfactory mucosal autograft placement. Rehabilitation focused on lower extremity stepping continued post-operatively	11/20 patients had ASIA improvement (6A → C, 3B → C, 2A → B) with 1/20 having ASIA decline (B → A). 15/20 with new voluntary EMG
Cristante et al[35], 2009	Chronic C/T-SCI	39	Apheresis for isolation of CD34+ bone marrow mononuclear stem cells-injected endovascularly via intercostal arteries or vertebral arteries	26/39 patients showed recovery of SSEP to peripheral stimuli
Pal et al[36], 2009	Subacute to Chronic C/T SCI	30	BM-MSC expanded ex-vivo and injected via LP	Injection safe with no adverse events
Mackay-Sim et al[37], 2008	Chronic complete T-SCI	6	Nasal biopsy for isolation of OESC, cultured for 4-10 wks. Laminectomy, durotomy and injection into damaged spinal cord and proximal/distal ends of lesion with a table mounted stereotactic injection apparatus	No adverse events, 1 of 6 patients with an improvement of 3 segments in LT/PP
Chernykh et al[38], 2007	Chronic C/T/L SCI	18	Purified BM-MSCs injected into the cystic lesion cavity and given intravenously	Motor and sensory improvement was equivocal, spasticity was significantly improved by BM-MSC injection
Lima et al[13], 2006	Chronic C/T-SCI	7	Laminectomy, with scar excision with suturing graft loaded with olfactory tissue to meninges/superficial tissue layers	2 patients went from ASIA-A to ASIA-C (out of 7 total) with return of bladder sensation/VAC
Callera et al[39], 2006	Chronic SCI	10	BM-MSCs injected via LP	Injection safe with no adverse events

C: Cervical; T: Thoracic; L: Lumbar; ISNCSCI: International Standards for the Neurological Classification of Spinal Cord Injury; ASIA: American Spinal Injury Association Impairment Scale; MSC: Mesenchymal stem cells; ADMSC: Adipose derived mesenchymal stem cells; BMC: Bone marrow cells; BM-MSCs: Bone marrow-derived mesenchymal stem cells; SEP: Somatosensory evoked potentials; MEP: Motor evoked potentials; HSC: Hematopoietic stem cell; GM-CSF: Granulocyte macrophage colony stimulating factor; Subq: Subcutaneous; LT/PP: Light touch/pinprick; VAC: Voluntary anal contraction; SCI: Spinal cord injury; UEMS: The European Union of Medical Specialists; CT: Computed tomography; EMG: Electromyography; OESC: Ovarian epithelial serous cystadenocarcinoma; UIT: U-shaped skin incision technique; CNS: Central nervous system; UC: Ulcerative colitis; UE: Upper-extremity; MRI: Magnetic resonance imaging.