Additional Table 3.
Published clinical trials of stem cell therapy for CP
| Study | Sample size/number of group | Age (yr) | Type of CP | Type of stem cells | Infusion route and dose | Course | Adverse events | Assessment tool | Improvement |
|---|---|---|---|---|---|---|---|---|---|
| Nguyen et al. (2ol7) | 4o/l | 2-l5 | Spastic | Autologous BMMNCs and CD3 4+ cells | 1st time, IT: 27.2 x 106 and 2.6 x 106/kg, respectively; 2nd time, IT: 17.1 x 106and 1.7 x 1 06/kg, respectively |
2 times with an interval of 3 mon | Mild fever (30%),intermittent vomiting (22.5%) | GMFM and MAS | Muscle spasticity, gross motor function |
| Sharma et al. (2ol5) | 4o/l | l7mon-22 | All types | Autologous BMMNCs | IT: 10.23 x 106 | Once | Spinal headache (15%), nausea (7.5%), vomiting (30%), pain at the site of injection (30%) and diarrhea (2.5%), seizure (5%) | PET-CT, GMFCS | Sitting/standing/walking balance, distal hand movements, neck holding, oromotor skills, cognition, leg movements, speech, ambulation, muscle tone ofthe upper limb/lower limb/trunk, overhead activities, dystonia |
| Nguyen et al. (2ol8) | 3o/l | 2-l5 | Bilateral paresis, hemiplegia | Autologous BMMNCs | IT: a volume of 8 mL/kg to 200 mL maximum | 2 times with an interval of 3 mon | No | GMFM, MAS, CP QOL-Child | Gross motor function, muscle spasticity, social well-being and acceptance; feelings about functioning; participation and physical health; emotional well-being; pain and impact of disability; family health |
| Zali et al.(2ol5) | l2/l | 4-l2 | Ataxic,athetoid, spastic | CD133+enriched bone marrow progenitor cells | IT: 4.5-17.6 x 106 | Once | Headache (41.7%),nausea and vomiting (41.7%), back pain (91.7%), seizure (8.3%) | GMFM, GMFCS, United Kingdom FIM+ FAM, BBS, MAS, MRI, EEG |
Motor function, spasticity and cognitive |
| Mancías-Guerra et al.(2ol4) | 18/l | l mon -8 | Quadriplegic,triplegic,hypotonic paralysis, paraplegic | Autologous TNCs and CD34+cells | IT: 13.12 x 108range (4.83-53.87 x 108 )TNCs and 10.02 x 106 (range, 1.02-29.9 x 106) CD34+ cells ; IV: 6.01 x 108 (range, 1.36-17.85 x 108) TNCs and 3.39 x 106 CD34+ cells | Once | Fever (5.6%),headache (11.1%),vomiting (11.1%), neck stiffness (5.6%), lingual edema (5.6%), laryngeal stridor (5.6%) | BDI, MRI | Cognitive, adaptive,personal-social, motor and communication |
| Zhang et al. (2015) | 1/1 | 6/12 | Not available | Allogenic hUC B-MSCs | IV: 5 x 107 | 4 times with an interval of a week, and repeated 4 times with an interval of a half year | No | Ashworth spasm assessment, GMFM,MRI, EEG, CDCC,comprehensive function | Gross motor function, language,self-dependence, cognitive ability, and social, adaptation |
| Okur et al. (2018) | 1/1 | 6 | Dystonic,spastic | Allogenic hUCB-MSCs | IT + IV: 15 x 106 | 4 times with an interval of 15 d | Mild back pain | FIM, GMFCS,MACS, CFSS,Tardieu Scale, TCMS | Gross motor function,self-dependence, trunk control and sitting balance, communication, hand skill |
| He et al.(2012) | 24/1 | 1 mon-7 | Quadriplegic,diplegia,dyskinetic,mixed | Neural stem cells | SS: 3.8 x 106- 7.3 x 107 | Once | Experienced fever (29.2%), vomited (4.2%), sphenotresia (29.2%) | EEG, MRI | Muscular tension in the limbs,the head-controlling action,visual acuity, the communicative competence |
| Chen et al. (2013) | 60/2 | 1-35 | Not available | Neural stem cell-like cells | IT: 1-2 x 107 | 2 times with an interval of 3 weeks | Crying | GMFM, Gesell questionnaire | Gross motor function |
| Rah et al.(2017) | 57/2 | 2-10 | Diplegia,hemiplegia,,triplegic,ataxic,athetoid | PBMCs | Ml ‡: 4.63 ±2.88 x 10s TNCs and 1.92 ± 1.99 x 106 CD34+ cells; M7 ‡: 6.20 ± 1.94 x 10s TNCs and 1.75 ±1.07 x 106CD34+cells | Once | Fever (3.5%),Irritability (1.8%),transient hemoglobinuria (5.3%), abdominal pain (1.8%) | GMFCS, GMFM,PEDI, QUEST,DDST-II, MRI,PET-CT | Gross motor function, fine motor function, detailed developmental |
| Wang et al. (2013) | 52/2 | 6 mon-15 | Athetoid,spastic,athetoid/spastic | Autologous BM-MSCs | IT + SS: 2 x 107 | Protocol I †:intrathecal infusion twice and stereot actic surgery once;Protocol 2†:intrathecal infusion 4 times. All the interval was 5 d | Low fever (<37.5°C) and wound aches | GMFM, GMFCS | Gross motor function, the muscular tension, lumbar muscular power and salivation decrease |
| Huang et al. (2018) | 54/2 | 3-12 | Not available | hUCB-MSCs | IV: 5 x 107 | 4 times with an interval of 1 wk, and repeated once 3 m on later | Upper respiratory tract infection diarrhea, anorexia,constipation | CFA | Gross motor ability and comprehensive function including cognizance, language competence, self-care, motor function, and social adaptability |
| Luan et al. (2012) | 94/2 | 2-17 mon | Quadriplegic,diplegia,dyskinetic,mixed | NPCs | SS: 8-10 x 106 | Once | Low-grade fever,tiny foci (6.4%) hemorrhage (1.1%), had difficulty in falling asleep within 1-3 d | GMFM, PDMS-FM | Gross motor function, fine motor function, Psychomotor functions |
| Chen et al. (2010) | 14/2 | 1-12 | Not available | OECs | SS: 2 x 106 | Once | No | GMFM, CQS | Neurological function and overall health status |
| Liu et al. (2017) | 105/3 | 6 mon-12.5 | Spastic | BMMNCs and BM-MSCs | IT: 1 x 106/kg | 4 times with an int erval of 3-4 d | Low intracranial pressure reactions: fever | GMFM, FMFM | Gross motor function, fine motor function |
| Thanh et al. (2019) | 25/1 | 2-15 | Spastic | BMMNCs + CD34+ cells | 1st time, IT: 17.4 ±11.9 x 106 and 1.5 ± 1.4 x 106; 2nd time, IT: 15.0 ± 12.8 x 106and 1.1 ± 1.1 x 106 | Twice with an interval of 6 mon | Vomiting (32%), local pain (16%), mild fever without any identified infection (4%) | GMFM, GMFCS, MRI, EEG | Gross motor function and a significant decrease in muscle tone values |
| Dong et al. (2018) | 1/1 | 4 | Not available | UC-MSCs | 1st time: 7.0 x 106/IT + 5.6 x 106/IV; 2nd time: 1.625 x 107/IT + 3.6 x 106/IV; 3rd time: 2.05 x 107/IT | 3 times | Not provided | EEG, MRI | EEG and limb strength, motor function, and language expression. The improvement in intelligence quotient was less obvious. |
| Min et al. (2013) | 105/3 | 10mon-10 | Spastic | UCB-TNC | IV: at least 3 x 107/kg | Once | Serious: Pneumonia(2. 9%), Influenza(2.9%), Death (2.9%); other: upper respiratory tract infection (51.4%), fever (34.3%), loose stool and diarrhea, pneumonia, nausea and vomiting (17.1%), dyspepsia, anorexia, constipation (14.3%), irritability, bronchitis (11.4%), apnea (8.6%), febrile convulsion, urticaria, hirsuitism (5.7%), seizure, alopecia, acute otitis media, anemia (2.9%) (only potentiated UCB group) | GMPM, GMFM, BSID-II, WeeFIM, PEDI, MRI, 18F-FDG-PET/CT | Ameliorated motor, cognitive impairment, self-care |
| Sun et al. (2017) | 63/2 | 1-6 | Hypotonic paralysis, spastic | UCB-TNC | IV: 1-5 x 107/kg | Once | Hives+/- low-grade fever (1.6%) | GMFM, PDMS-2 GMQS, GMFCS, MRI | Gross motor skills connectivity |
| Gu et al. (2020) | 40/2 | 2-12 | Not available | UC-MSC | IV: 4.5-5.5 x 107 | 4 times with an int erval of 7 d | Upper respiratory infection (61.54%), diarrhea (38.46%), fever (28.21%), vomiting (20.51%), constipation (10.26%) | GMFM, activities of daily living CFA, 18F-FDG-PET/CT,, MRI | Gross motor and cognitive function |
† Protocol 1: child’s age were ≥ 5 years old or head circumference ≥50 cm; Protocol 2: child’s age were < 5 years old or head circumference < 50 cm. ‡ M1: PBMCs first and placebo 6 months later, M7: placebo first and PBMCs 6 months later. BMMNCs: bone marrow mononuclear stem cell; BM-MSC: bone marrow-derived mesenchymal stromal cell; CP: cerebral palsy; TNC: total nucleated cell; PBMC: peripheral blood mononuclear cell; hUCB-MSC: human umbilical cord blood mesenchymal stem cell; NPC: neural progenitor cell; OEC: olfactory ensheathing cell; UC-MSC: umbilical cord mesenchymal stem cell; UCB: umbilical cord blood; IT: intrathecal; IV: intravenous; SS: stereotactic surgery; GMFM: Gross Motor Function Measure; MAS: Modified Ashworth Score; GMFCs: Gross Motor Function Classification System; CP QOL-Child: Cerebral Palsy Quality of Life Questionnaire for children; FIM: Functional Independence Measure; FAM: Functional Assessment Measure; BBS: Berg Balance Scale; BDI: Battelle Developmental Inventory; GMPM: gross motor performance measure; CDCC: CDCC Infant Mental Development Scale; MACS: manual ability classification system; CFSS: Communication Function Classification System; TCMS: Trunk Control Measurement Scale test; PEDI: pediatric evaluation of disability inventory; QUEST: quality of upper extremity skill test; DDST-II: Denver development screening test II; CFA: comprehensive function assessment; PDMS-FM: Peabody Developmental Motor Scale-Fine Motor test; CQS: Caregiver Questionnaire Scale; FMFM: Fine Motor Function Measure; BSID-II: Bayley scales of infant development-II Mental and Motor scales; WeeFIM: functional independence measure for children; PDMS-2 GMQS: Peabody Developmental Motor Scales-2 Gross Motor Quotient scores; PET-CT: positron emission tomography-computed tomography; MRI: magnetic resonance imaging; 18F-FDG-PET/CT: 18F-fluorodeoxyglucose positron emission tomography; EEG: electroencephalogram.