Safety

Research

The safety and tolerability of stem cell therapy has been clearly demonstrated in numerous studies involving large numbers of patients treated for a variety of conditions. Common conditions treated with stem cell therapy include orthopedic conditions such as osteoarthritis, heart disease, stroke, multiple sclerosis, autism, cerebral palsy and others.

Based on the early human clinical trials there appears to be a strong argument for the safe use of intravenous stem cell therapy in the treatment of various common conditions. While we wait for phase II/III trials the current data is encouraging and supports use of stem cell therapy in the clinical setting.

The purpose of the “Safety Research Archive” is to highlight recent clinical studies demonstrating the safety of stem cell therapy in a format that is quick and easy to review. More detailed summaries of these studies can be found in our Reseach Archive.

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Safety Research Sections

Osteoarthritis  |  Cardiovascular  |  Stroke  |  Multiple Sclerosis  |  Autism  |  Cerebral Palsy  |  Derived Stem Cells  |  References

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Osteoarthritis and the Safety of Stem Cell Therapy

In 2015 Centeno et al conducted a multicenter analysis of 2372 patients who received bone marrow derived stem cell therapy for various orthopedic conditions. The therapy was deemed safe and well tolerated due to observed low rates of reported adverse events and substantially lower rates of serious or treatment related adverse events.

A 2019 randomized controlled trial by Freitag et al involving 30 participants with knee osteoarthritis treated with adipose derived mesenchymal stem cells revealed no serious adverse events during 12 month follow up. Only two participants reported severe pain and swelling at injection site. They concluded that “Autologous ADMSC therapy appears to be a safe and effective therapy for knee osteoarthritis and may have the potential to prevent disease progression.”

In a 2019 double blind, randomized, self-controlled trial, by Hong et al observed no severe adverse events during 12 month follow up in 16 participants with knee OA treated with adipose derived stem cells (Stromal Vascular Fraction). Six participants reported pain and swelling at injection site. They concluded that “The results of this study suggest that autologous adipose-derived SVF treatment is safe and can effectively relief pain, improve function, and repair cartilage defects in patients with knee osteoarthritis.”

A 2019 double blind, randomized controlled trial by Lee et al also showed no serious adverse events during 6 month follow up in 24 participants with knee osteoarthritis treated with adipose derived mesenchymal stem cells. Treatment related adverse events were reported in eight participants; 6 joint pain and 2 joint swelling. They concluded that “An intra-articular injection of autologous AD-MSCs provided satisfactory functional improvement and pain relief for patients with knee osteoarthritis in the outpatient setting, without causing adverse events at 6 months’ follow-up.”

In 2019 Matas et al conducted a triple blind, randomized trial of 29 participants with knee osteoarthritis treated with umbilical cord mesenchymal stem cells and observed no serious adverse events during 12 month follow up. Common treatment related adverse events included acute synovitis, joint pain and swelling. They concluded that “Repeated UC‐MSC treatment is safe and superior to active comparator in knee OA at 1‐year follow‐up.”

In 2017 Bansal et al conducted a preliminary clinical study of adipose derived stromal vascular fraction stem cells and PRP in 10 patients with knee osteoarthritis and observed no serious adverse events during the 24 month follow up. One participant reported pain and swelling at harvest site and one participant developed acute synovitis. They concluded that “The procedure demonstrated a strong safety profile with no severe adverse events or complications reported.”

Cardiovascular Conditions and Safety of Intravenous Stem Cell Therapy

In 2019 Jayaraj et al conducted a systematic review with meta-analysis of 6 randomized, controlled trials involving 526 patients with advanced heart failure to assess safety and efficacy of stem cell therapy. Stem cell derived tissue used and route of delivery was not uniform among studies. They found no difference in risk for all-cause mortality between treatment and control groups, and most trials reported no or did not report treatment related complications such as arrhythmia, stroke or heart attack. Jayaraji et al concluded that the safety results from this review correlate well with previous meta-analysis. “The safety analysis indicates no increased risk of mortality in patients with advanced heart failure.”

In 2018 Lalu et al conducted a systematic review of 23 studies involving 1,148 patients with acute heart attack or ischemic heart failure to assess the safety and efficacy of stem cell therapy. Stem cell derived tissue used and route of delivery was not uniform among studies. They observed no association between stem cells and acute adverse events in all 23 studies and no difference in risk of mortalities between treatment and control groups. They concluded that “Results from our systematic review suggest that MSC therapy for ischemic heart disease appears to be safe.”

In 2017 Bartolucci et al conducted a double blind, randomized, placebo-controlled trial to evaluate safety and efficacy of IV umbilical cord derived mesenchymal stem cells in 30 patients with chronic heart failure. They observed no acute treatment related adverse events, no significant differences in adverse events between placebo and treatment group and no significant abnormalities in laboratory tests during the 12 month follow up. They concluded that “Intravenous infusion of UC-MSC was safe in this group of patients with stable heart failure and reduced ejection fraction under optimal medical treatment.”

In 2017 Butler at el conducted a single blind, placebo controlled, crossover, randomized phase IIa trial to assess the safety and preliminary efficacy of intravenously administered bone marrow derived ischemia-tolerant mesenchymal stem cells (itMSCs) in 22 patients with non-ischemic cardiomyopathy. Butler et al observed no major differences in death, hospitalization or serious adverse events between groups. There was one treatment related adverse event related to bruising at intravenous infusion site. Butler et al concluded “overall, this study found a single dose of intravenous itMSCs to be safe, to be well-tolerated, and to provide clinically relevant signals for efficacy.”

In 2016 Nguyen et al conducted a systematic review of 29 randomized, controlled trials involving 2817 patients with heart failure and ischemic heart disease. Stem cell derived tissue used and route of delivery was not uniform among studies. No serious adverse events after intracoronary or IV stem cells in acute heart attack and ischemic heart disease. Two studies using skeletal myoblast cells reported acute arrhythmias. They concluded that “Safe delivery of cells has been demonstrated in both preclinical and clinical trials.”

A 2016 systematic review by Fisher et al of 38 studies involving 1907 patients with ischemic heart disease and congestive heart failure demonstrated safety of stem cell therapy. Stem cell derived tissue used and route of delivery was not uniform among studies. They found serious adverse events during mapping or injection procedure were infrequent, early postoperative serious adverse events were rare and adverse events associated with bone marrow aspiration were rare.

In a small 2016 study to assess safety and efficacy of IV umbilical cord derived mesenchymal stem cells in 3 patients with systolic heart failure, Fang et al observed no complications, adverse events or serious adverse events during the 12 month follow up. No cases of distal coronary artery occlusion, acute cardiac dysfunction and ventricular arrhythmia occurred.

Stroke and Safety of Intravenous Stem Cell Therapy

In 2019 Vahidy et al demonstrated the safety of intravenous bone marrow derived mononuclear stem cells in the treatment of 25 patients with acute ischemic stroke. All patients successfully completed the study intervention and no treatment related serious adverse events were observed in the 12 month follow up. Of 31 treatment related adverse events 28 were grade 1 (mild) and ten of the 31 were due to harvest procedure. They concluded that “Bone marrow harvest and infusion of MNCs is safe and feasible in patients with acute ischemic stroke.”

In 2019 Levy et al assessed safety and preliminary efficacy of IV bone marrow derived stem cells in 36 patients with chronic stroke. Treatment was deemed safe based on serial examinations, ECG, laboratory tests, imaging studies and reported of adverse events. 15 serious adverse events were reported and none were ‘possibly’, ‘probably’ or ‘related’ to treatment. Two Grade 1 adverse events were ‘possibly related’ to treatment and included urinary tract infection and irritation at IV site. They concluded that “Intravenous transfusion of allogeneic ischemia-tolerant mesenchymal stem cell in patients with chronic stroke and substantial functional deficits was safe.”

In 2018 Laskowitz et al assessed the safety and feasibility of IV umbilical cord blood in 10 adult patients with acute ischemic stroke. Of 113 reported adverse events, 112 were classified as “unrelated to treatment” to treatment. They concluded that this therapy was safe and well tolerated in these patients. They concluded that “Data suggest that a single i.v. dose of allogeneic non-HLA matched human UCB cells is safe in adults with ischemic stroke.”

In 2018 Xue et al conducted a systematic review including 23 studies with 1,279 patients with ischemic stroke. Stem cell derived tissue used and route of delivery was not uniform among studies. No serious adverse events were reported in the follow up period which ranged from 1 to 60 months. The most common adverse events were headache and fever which resolved within 24 hr without treatment. They concluded that “MSC therapy is safe and effective in treating ischemic stroke.”

In 2017 Hess et al conducted a double blind randomized placebo controlled trial to identify the highest, well-tolerated and safest single intravenous dose of bone marrow derived stem cells (progenitor cells) and to evaluate its efficacy in 67 patients with moderately severe acute ischemic stroke. The primary safety endpoint of this study was dose limiting toxicity effects. This endpoint was achieved and safety was confirmed as there were no toxic events, no allergic reactions and no differences in adverse events between treatment and placebo groups. Hess et al concluded that stem cell therapy with “multipotent adult progenitor cells were safe and well tolerated in patients with acute ischemic stroke.”

In 2015 Taguchi et al conducted a small non-randomized, clinical trial to assess the feasibility and safety of intravenous bone marrow derived mononuclear cells (BM-MNCs), a diverse population of cells that include stem cells, in treating 12 who experienced a severe embolic stroke. Primary safety outcome was worsening of NIHSS score and secondary safety outcome was death at the time of discharge. Serious adverse events were observed in two patients over 6 month follow up; one had aspiration pneumonia and sepsis which was deemed not related to cell therapy and the other had recurrent stroke which was deemed unclear if it was associated with cell therapy. This was the only patient who had a decreased NIHSS score. No patients experienced death at discharge. Taguchi et al concluded that “our study demonstrates that intravenous administration of autologous bone marrow mononuclear cells to patients with severe embolic stroke was feasible and safe.”

Multiple Sclerosis and Safety of IV Stem Cell Therapy

In 2019 Riordan et al conducted an open-label, single arm phase I/II study to assess the safety and efficacy of intravenous umbilical cord derived mesenchymal stem cells (UCMSCs) in 20 patients with Multiple Sclerosis (MS). 72 adverse events were reported with six classified as moderate severity and the remaining as mild. None of the adverse events were deemed ‘definitely’ related to study. The most common adverse events were headache and fatigue. There were no serious adverse events and no deaths occurred. Riordan et al concluded that “the intravenous infusion of UCMSC over several days is safe in subjects with MS.”

In 2018 Meng et al conducted a small clinical trial to assess the safety and efficacy of repeated intravenous infusions of umbilical cord derviced mesenchymal stem cells (UCMSCs) in 2 patients with multiple sclerosis (MS). Safety was assessed using physiological examination including routine blood, urine and stool tests, electrocardiography, chest xray and frequency and severity of adverse events. All physiological examinations revealed normal indexes. Adverse reactions included fever, dizziness, headache, skin redness and vascular irritation which mainly occurred during infusion. Fever was the most common adverse reaction which resolved without medical intervention within 36 hours. Toxic reactions to treatment were not detected during the 8 year follow up.

In 2018 Fernandez et al conducted a triple blinded, placebo controlled, randomized phase I/II trial to assess the safety and feasibility of a single intravenous infusion of adipose derived mesenchymal stem cells (ADMSC) in the treatment of patients with advanced secondary progressive multiple sclerosis (SPMS). Safety was assessed by monitoring adverse events, vital signs, spirometry and standard laboratory measures. A total of 70 adverse events were reported during the trial period. The most frequent adverse events were urinary tract infections, respiratory infection and anemia. Four serious adverse events were reported and none of them were considered to be related to treatment. No tumor formation was reported in the 12 month follow up. There were no significant changes in vital signs, spirometry and laboratory values. However, the low dose group showed a significant decrease in cholesterol and improved kidney function measured by a decrease of creatinine. Fernandez et al concluded that “the present study demonstrates that infusion of AdMSCs is a safe and feasible procedure in patients with SPMS.”

In 2018 Cohen et al conducted an open-label, phase 1 study to assess the feasibility, safety and tolerability of an single intravenous infusion of autologous, culture expanded bone marrow derived mesenchymal stem cells (BMMSCs) in 24 patients with MS. Safety was evaluated by assessing adverse events, vital signs, and various laboratory tests including routine blood tests, immune system markers, and inflammatory markers. Chest Xray and electrocardiogram (EEG) were also performed. There were no severe or serious adverse events related to stem cell therapy. No patients developed clinical or laboratory indications of autoimmune phenomena and none had clinical or radiological evidence of paradoxical disease activation of MS. The most commonly reported adverse events were muscle spasticity, urinary tract infection and fall. Cohen et al concluded that “this phase 1 trial supports the feasibility, safety and tolerability of autologous MSC transplantation in MS.”

In 2013 Li et al conducted a randomized, two armed study to assess the safety and efficacy of repeated intravenous human umbilical cord derived mesenchymal stem cells (hUC-MSC) in addition to conventional treatment in 13 patients with MS. Safety assessment included physical examination, adverse events and quarterly brain MRI. The clinical safety was demonstrated without any reported significant adverse effects during 12 month follow up. Brain MRI results were not discussed in results section. Li et al concluded that “During a 1-year observation, no significant adverse effects were found, indicating the clinical safety could be well accepted.

In 2014 Llufriu et al conducted a randomized, double blinded, crossover placebo controlled phase II trial investigating the efficacy of a single intravenous infusion of bone marrow derived mesenchymal stem cells (BMMSCs) in 9 patients with relapsing remitting multiple sclerosis (RRMS). All reported adverse events were graded as mild and were deemed not to be related to treatment. No serious adverse events were reported during the study or at 12 month follow up. Delayed adverse events were also not observed. Llufriu et al concluded that “Bone-marrow-MSCs are safe and may reduce inflammatory MRI parameters supporting their immunomodulatory properties.”

Autism and Safety of IV Umbilical Cord Tissue Stem Cell Therapy

In 2019 Riordan et al conducted a clinical trial to assess the safety and efficacy of intravenous infusions of umbilical cord derived mesenchymal stem cells (UCMSCs) in 20 patients with ASD. Over 12 month follow up period most of the adverse events were ‘not related’ or ‘not likely related’ to stem cell treatment. Adverse events related to treatment were mild or moderate and short in duration. They included mild inflammation, swelling and/or redness at infusion site, mild fatigue, headache, fever, etc. which are commonly reported in treatments with stem cells. There were no treatment related serious adverse events. Riordan et al concluded that “The administration of repeated-dose UC-MSC infusions is safe and tolerable for patients with ASD.”

In 2018 Chez et al conducted a trial to assess the safety of a single intravenous infusion of autologous umbilical cord blood (AUCB) in 29 patients aged 2 to 6 years old with ASD and to document changes in language, social behavior and learning. The results of this study showed that treatment with intravenous AUCB was safe in children with ASD. Over the 24 week follow up period, there were minimal treatment related adverse events and none required treatment. There were no allergic reactions and no serious adverse events associated with the treatment. Chez et al concluded that “The present study provided further evidence that treatment with AUCB is safe.”

In 2017 Dawson et al conducted a trial to assess the safety and efficacy of a single intravenous infusion of autologous umbilical cord blood (AUCB) in 25 children aged 2-6 years old with ASD. The results of this study showed that treatment with intravenous AUCB was safe and well tolerated. Over the 12 month follow up period, all adverse events were either mild or moderate and there were no serious adverse events or treatment related infections reported. The most common treatment related adverse events was allergic reaction (Itchy skin and/or cough) and the most common unrelated adverse events were agitation, skin changes and typical childhood infections. Dawson et al concluded that “intravenous infusion of autologous umbilical cord blood in young children with ASD is safe and feasible.”

In 2013 Lv et al conducted a trial to assess safety and compare the efficacy of cord blood derived mononuclear cells (CBMNCs) and umbilical cord derived mesenchymal stem cells (UCMSCs) with rehabilitation therapy in 23 patients with Autism. Transplantation of stem cells included intravenous and intrathecal injections. During the 24 week follow up period, there were no allergic reactions, no serious adverse events and no significant changes in laboratory tests between groups. Five patients experienced transient low grade fever and recovered without medical intervention. Lv et al demonstrated that stem cell therapy is safe and well tolerated by patients with autism.

Cerebral Palsy and Safety of IV Stem Cell Therapy

In 2018 Huang et al conducted a randomized, placebo controlled trial to assess the safety and efficacy of repeated intravenous infusions of umbilical cord blood derived mesenchymal stem cells (UCBMSCs) and basic rehabilitation therapy in 27 children aged 3-12 years old with CP. MRI results showed no sign of cerebral tumor formation and there were no serious adverse events observed during the 24 month follow up. Upper respiratory tract infection and diarrhea were the most frequently reported non-serious adverse event, none of which influenced the study. Huang et al concluded that “”UCB-MSC infusion with basic rehabilitation was safe and effective to improve gross motor function in children with CP.”

In 2017 Sun et al conducted a double-blind, placebo-controlled, crossover study to assess the safety and efficacy of a single intravenous infusion of autologous umbilical cord blood (aUCB or ACB) in 32 children aged 1 to 6 years old with CP. There were no serious adverse events related to treatment. One patient experienced an infusion reaction to both placebo and ACB treatment which consisted of hives and low grade fever. The reaction resolved with additional anti-histamine medication. Sun et al demonstrated that stem cell therapy was safe and well tolerated without serious adverse events.

In 2016 Novak et al performed and systematic review and meta-analysis to assess safety and efficacy of stem cell therapy in patients with cerebral palsy (CP). Five clinical trials involving 328 patients were included. Cell types, cell dose and delivery route were not uniform. There were similar adverse events between treatment and control groups. Fever was a commonly reported adverse event and occurred evenly between groups. Low rates of serious adverse events among trials suggest an acceptable risk to benefit ratio. Stem cell therapy was determined to be safe, and well tolerated in all trials.

In 2015 Romanov et al performed a post-registration clinical study to evaluate the safety and efficacy of repeated intravenous infusions of allogeneic umbilical cord blood (UCB) in 80 children aged 1-12 years old with cerebral palsy (CP). Severe forms of CP were prevalent in this study with 50% of patients being tetraplegic. Follow up period ranged from 3 months to 3 years. Infusion with UCB was well tolerated, and no acute or delayed adverse reactions were observed. Romanov et al concluded that “this study has demonstrated the safety and efficacy of allogeneic AB0/Rh-identical UCB cells in young patients suffering from CP.”

In 2015 Kang et al conducted a randomized, placebo controlled, double blind trial to assess the safety and efficacy of intravenous or intra-arterial infusions of umbilical cord blood (UCB) in 17 patients aged 6 months to 20 years old with cerebral palsy (CP). No serious adverse events occurred in this study. Additional data on safety and adverse events was limited.

In 2013 Min et al conducted a double-blind, randomized, placebo-controlled trial to compare the efficacy of a single intravenous umbilical cord blood (UCB) infusion with or without erythropoietin (EPO) injections in 64 children with cerebral palsy (CP) undergoing rehabilitation therapy. Ten serious adverse events that required hospitalization were reported evenly between treatment and control groups. Pneumonia and irritability were the most frequent non-serious adverse events in the group that received UCB infusion with EPO. There were no prolonged or delayed serious adverse events reported at 1 year follow up. Min et al concluded that “Considering the overall frequency and severity of the adverse effects in this study, the risks did not appear to be prohibitive in considering this new approach for CP.”

In 2012 Lee et al conducted a pilot study to assess the safety and feasibility of a single intravenous infusion of autologous cord blood mononuclear cells (CBMNCs) in 20 children, 2-10 years of age with cerebral palsy (CP). Safety was assessed by monitoring vitals, symptoms related to toxicity, neurodevelopment tests and frequency of adverse events. Infusion was generally well-tolerated with minimal adverse events which were controlled with medication and intravenous hydration. Lee et al concluded that “autologous intravenous CB MNC infusion seems to be practicable and safe and has yielded potential benefits in children with CP.”

Safety of Adipose-Derived and Umbilical-Cord-Derived Stem Cells

In 2017 Toyserkani et al performed a systematic review to assess the safety of adipose derived cell therapy in the treatment of any disease. They included 70 studies involving 1,474 patients with a follow up period ranging from less than one month to 3 years to assess safety. Various different diseases were involved in this review including cardiovascular disease, immunological disease, gastrointestinal disease and many others. Cell dose, source of cells and route of administration were not standardized among trials. The most common route of administration was intravenous. Safety analysis included adverse events with a focus on thromboembolic, mortality, immunological, and oncological safety concerns. Very few adverse events related directly to cell therapy were reported. Most adverse events were related to harvesting procedure, trauma associated with injection, or natural progression of disease. Of all the studies included only one case of pulmonary embolism and few cases of heart attack and stroke were described in patients with cardiovascular disease and poor prognoses. Regarding immunological safety two studies that evaluated the long term production of donor specific anti-bodies found that 19-34% of patients developed such anti-bodies after treatment suggesting an immune response. The consequence of this, if any, still remains unknown. Overall, there was no evidence of graft versus host disease or immune responses that negatively affected the therapeutic response. For studies that included a control group there was no indication of increased mortality in patients who received cell therapy. The oncological safety was evaluated in 5 studies administering stem cells in the setting of previous malignancy; 3 prostate cancer and 2 breast cancer. Only one case of local breast cancer recurrence was identified among 121 breast cancer patients. The remaining studies observed no recurrence within the follow up period. Toyserkani et al concluded that “Adipose-derived cell therapy has so far shown a favorable safety profile.”

In 2017 Can et al performed a systematic analysis of clinical trials using umbilical cord mesenchymal stromal cell (UC-MSC) therapy. They included 93 peer reviewed articles and abstracts that investigated the safety, efficacy and feasibility of UC-MSCs in 2001 patients with 53 distinct diseases. The types of studies, diseases, routes of administration, number of treatments and cell dose varied among trials. Thirty-four studies were published as single case or case reports. Disease categories included neurologic, hematologic, immunologic, cardiac, endocrine, pulmonary, and others. Intravenous route of administration was the most common among trials followed by intra-arterial injection. Fifty trials used single treatment and the remaining used 2 or more treatments. Cell dose varied between 0.2 × 10^6/kg and 8.68 × 10^6 /kg. Seventy-two percent of the trials included reported the safety of intervention without serious acute and/or chronic adverse events. No incidences of tumor formation or cell rejection were reported. Headaches, fever, dizziness, and local pain were occasionally reported in the remaining trails. All the studies in the endocrine category demonstrated that UC-MSC was safe in type 1 and type 2 diabetes. Studies in the cardiovascular category conclusively demonstrated that UC-MSC transplantation is safe. None of the studies investigating UC-MSCs in liver disease showed any long term adverse effects. However a self-limiting, short term fever was observed in four studies.

References

Sources for Osteoarthritis Studies:

• Centeno, C. J., Al-Sayegh, H., Freeman, M. D., Smith, J., Murrell, W. D., & Bubnov, R. (2016). A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions. International Orthopaedics, 40(8), 1755–1765. https://doi.org/10.1007/s00264-016-3162-y
• Freitag, J., Bates, D., Wickham, J., Shah, K., Huguenin, L., Tenen, A., … Boyd, R. (2019). Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: A randomized controlled trial. Regenerative Medicine, 14(3), 213–230. https://doi.org/10.2217/rme-2018-0161
• Hong, Z., Chen, J., Zhang, S., Zhao, C., Bi, M., Chen, X., & Bi, Q. (2019). Intra-articular injection of autologous adipose-derived stromal vascular fractions for knee osteoarthritis: a double-blind randomized self-controlled trial. International Orthopaedics, 43(5), 1123–1134. https://doi.org/10.1007/s00264-018-4099-0
• Lee, W. S., Kim, H. J., Kim, K. Il, Kim, G. B., & Jin, W. (2019). Intra-Articular Injection of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis: A Phase IIb, Randomized, Placebo-Controlled Clinical Trial. Stem Cells Translational Medicine, 8(6), 504–511. https://doi.org/10.1002/sctm.18-0122
• Matas, J., Orrego, M., Amenabar, D., Infante, C., Tapia-Limonchi, R., Cadiz, M. I., … Espinoza, F. (2019). Umbilical Cord-Derived Mesenchymal Stromal Cells (MSCs) for Knee Osteoarthritis: Repeated MSC Dosing Is Superior to a Single MSC Dose and to Hyaluronic Acid in a Controlled Randomized Phase I/II Trial. Stem Cells Translational Medicine, 8(3), 215–224. https://doi.org/10.1002/sctm.18-0053
• Bansal, H., Comella, K., Leon, J., Verma, P., Agrawal, D., Koka, P., & Ichim, T. (2017). Intra-articular injection in the knee of adipose derived stromal cells (stromal vascular fraction) and platelet rich plasma for osteoarthritis. Journal of Translational Medicine. https://doi.org/10.1186/s12967-017-1242-4

Sources for Cardiovascular Studies:

• Fang, Z., Yin, X., Wang, J., Tian, N., Ao, Q., Gu, Y., & Liu, Y. (2016). Intravenous Allogeneic Mesenchymal Stem Cells for Nonischemic Cardiomyopathy: Safety and Efficacy Results of a Phase II-A Randomized Trial Experimental and Therapeutic Medicine, 12(5), 3328–3332. https://doi.org/10.3892/etm.2016.3748
• Fisher, S. A., Doree, C., Mathur, A., Taggart, D. P., & Martin-Rendon, E. (2016). Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. The Cochrane Database of Systematic Reviews, 12, CD007888. https://doi.org/10.1002/14651858.CD007888.pub3
• Nguyen, P. K., Rhee, J. W., & Wu, J. C. (2016). Adult stem cell therapy and heart failure, 2000 to 2016: A systematic review. JAMA Cardiology, Vol. 1, pp. 831–841. https://doi.org/10.1001/jamacardio.2016.2225
• Butler, J., Epstein, S. E., Greene, S. J., Quyyumi, A. A., Sikora, S., Kim, R. J., … Gheorghiade, M. (2017). Intravenous Allogeneic Mesenchymal Stem Cells for Nonischemic Cardiomyopathy: Safety and Efficacy Results of a Phase II-A Randomized Trial. Circulation Research, 120(2), 332–340. https://doi.org/10.1161/CIRCRESAHA.116.309717
• Bartolucci, J., Verdugo, F. J., González, P. L., Larrea, R. E., Abarzua, E., Goset, C., … Khoury, M. (2017). Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure: A phase 1/2 randomized controlled trial (RIMECARD trial [Randomized clinical trial of intravenous infusion umbilical cord mesenchymal. Circulation Research, 121(10), 1192–1204. https://doi.org/10.1161/CIRCRESAHA.117.310712
• Lalu, M. M., Mazzarello, S., Zlepnig, J., Dong, Y. Y. (Ryan), Montroy, J., McIntyre, L., … Fergusson, D. A. (2018). Safety and Efficacy of Adult Stem Cell Therapy for Acute Myocardial Infarction and Ischemic Heart Failure (SafeCell Heart): A Systematic Review and Meta-Analysis. Stem Cells Translational Medicine, Vol. 7, pp. 857–866. https://doi.org/10.1002/sctm.18-0120
• Jayaraj, J. S., Janapala, R. N., Qaseem, A., Usman, N., Fathima, N., Kashif, T., … Bakshi, S. (2019). Efficacy and Safety of Stem Cell Therapy in Advanced Heart Failure Patients: A Systematic Review with a Meta-analysis of Recent Trials Between 2017 and 2019. Cureus. https://doi.org/10.7759/cureus.5585

Sources for Stroke Studies:

• Taguchi, A., Sakai, C., Soma, T., Kasahara, Y., Stern, D. M., Kajimoto, K., … Nagatsuka, K. (2015). Intravenous Autologous Bone Marrow Mononuclear Cell Transplantation for Stroke: Phase1/2a Clinical Trial in a Homogeneous Group of Stroke Patients. Stem Cells and Development, 24(19), 2207–2218. https://doi.org/10.1089/scd.2015.0160
• Hess, D. C., Wechsler, L. R., Clark, W. M., Savitz, S. I., Ford, G. A., Chiu, D., … Mays, R. W. (2017). Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet Neurology, 16(5), 360–368. https://doi.org/10.1016/S1474-4422(17)30046-7
• Xue, P., Wang, M., & Yan, G. (2018). Mesenchymal stem cell transplantation as an effective treatment strategy for ischemic stroke in Asia: a meta-analysis of controlled trials. Therapeutics and Clinical Risk Management, 14, 909–928. https://doi.org/10.2147/TCRM.S161326
• Laskowitz, D. T., Bennett, E. R., Durham, R. J., Volpi, J. J., Wiese, J. R., Frankel, M., … Kurtzberg, J. (2018). Allogeneic Umbilical Cord Blood Infusion for Adults with Ischemic Stroke: Clinical Outcomes from a Phase 1 Safety Study. Stem Cells Translational Medicine, 7(7), 521–529. https://doi.org/10.1002/sctm.18-0008
• Levy, M. L., Crawford, J. R., Dib, N., Verkh, L., Tankovich, N., & Cramer, S. C. (2019). Phase I/II Study of Safety and Preliminary Efficacy of Intravenous Allogeneic Mesenchymal Stem Cells in Chronic Stroke. Stroke, 50(10), 2835–2841. https://doi.org/10.1161/STROKEAHA.119.026318
• Vahidy, F. S., Haque, M. E., Rahbar, M. H., Zhu, H., Rowan, P., Aisiku, I. P., … Savitz, S. I. (2019). Intravenous Bone Marrow Mononuclear Cells for Acute Ischemic Stroke: Safety, Feasibility, and Effect Size from a Phase I Clinical Trial. STEM CELLS. https://doi.org/10.1002/stem.3080

Sources for Multiple Sclerosis Studies:

• Riordan, N. H., Morales, I., Fernández, G., Allen, N., Fearnot, N. E., Leckrone, M. E., … Paz Rodriguez, J. (2018). Clinical feasibility of umbilical cord tissue-derived mesenchymal stem cells in the treatment of multiple sclerosis. Journal of Translational Medicine, 16(1). https://doi.org/10.1186/s12967-018-1433-7
• Meng, M., Liu, Y., Wang, W., Wei, C., Liu, F., Du, Z., … Li, Q. (2018). Umbilical cord mesenchymal stem cell transplantation in the treatment of multiple sclerosis. American Journal of Translational Research, 10(1), 212 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801359/
• Fernández, O., Izquierdo, G., Fernández, V., Leyva, L., Reyes, V., Guerrero, M., … Research Group Study EudraCT 2008-004015-35. (2018). Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study. PloS One, 13(5), e0195891. https://doi.org/10.1371/journal.pone.0195891
• Cohen, J. A., Imrey, P. B., Planchon, S. M., Bermel, R. A., Fisher, E., Fox, R. J., … Lazarus, H. M. (2018). Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis. Multiple Sclerosis (Houndmills, Basingstoke, England), 24(4), 501–511. https://doi.org/10.1177/1352458517703802
• Li, J.-F., Zhang, D.-J., Geng, T., Chen, L., Huang, H., Yin, H.-L., … Wang, Y.-L. (2014). The Potential of Human Umbilical Cord-Derived Mesenchymal Stem Cells as a Novel Cellular Therapy for Multiple Sclerosis. Cell Transplantation, 23(1_suppl), 113–122. https://doi.org/10.3727/096368914×685005
• Llufriu, S., Sepúlveda, M., Blanco, Y., Marín, P., Moreno, B., Berenguer, J., … Saiz, A. (2014). Randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis. PLoS ONE, 9(12). https://doi.org/10.1371/journal.pone.0113936

Sources for Autism Studies:

• Lv, Y. T., Zhang, Y., Liu, M., Qiuwaxi, J. na ti, Ashwood, P., Cho, S. C., … Hu, X. (2013). Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. Journal of Translational Medicine, 11(1). https://doi.org/10.1186/1479-5876-11-196
• Dawson, G., Sun, J. M., Davlantis, K. S., Murias, M., Franz, L., Troy, J., … Kurtzberg, J. (2017). Autologous Cord Blood Infusions Are Safe and Feasible in Young Children with Autism Spectrum Disorder: Results of a Single-Center Phase I Open-Label Trial. Stem Cells Translational Medicine, 6(5), 1332–1339. https://doi.org/10.1002/sctm.16-0474
• Chez, M., Lepage, C., Parise, C., Dang-Chu, A., Hankins, A., & Carroll, M. (2018). Safety and Observations from a Placebo-Controlled, Crossover Study to Assess Use of Autologous Umbilical Cord Blood Stem Cells to Improve Symptoms in Children with Autism. Stem Cells Translational Medicine, 7(4), 333–341. https://doi.org/10.1002/sctm.17-0042
• Riordan, N. H., Hincapié, M. L., Morales, I., Fernández, G., Allen, N., Leu, C., … Novarro, N. (2019). Allogeneic Human Umbilical Cord Mesenchymal Stem Cells for the Treatment of Autism Spectrum Disorder in Children: Safety Profile and Effect on Cytokine Levels. Stem Cells Translational Medicine. https://doi.org/10.1002/sctm.19-0010

Sources for Cerebral Palsy Studies:

• Lee, Y.-H., Choi, K. V., Moon, J. H., Jun, H.-J., Kang, H.-R., Oh, S.-I., … Yang, Y.-S. (2012). Safety and feasibility of countering neurological impairment by intravenous administration of autologous cord blood in cerebral palsy. Journal of Translational Medicine, 10, 58. https://doi.org/10.1186/1479-5876-10-58
• Min, K., Song, J., Kang, J. Y., Ko, J., Ryu, J. S., Kang, M. S., … Kim, M. (2013). Umbilical cord blood therapy potentiated with erythropoietin for children with cerebral palsy: A double-blind, randomized, placebo-controlled trial. Stem Cells, 31(3), 581–591. https://doi.org/10.1002/stem.1304
• Kang, M., Min, K., Jang, J., Kim, S. C., Kang, M. S., Jang, S. J., … Kim, M. (2015). Involvement of Immune Responses in the Efficacy of Cord Blood Cell Therapy for Cerebral Palsy. Stem Cells and Development, 24(19), 2259–2268. https://doi.org/10.1089/scd.2015.0074
• Romanov, Y. A., Tarakanov, O. P., Radaev, S. M., Dugina, T. N., Ryaskina, S. S., Darevskaya, A. N., … Smirnov, V. N. (2015). Human allogeneic AB0/Rh-identical umbilical cord blood cells in the treatment of juvenile patients with cerebral palsy. Cytotherapy, 17(7), 969–978. https://doi.org/10.1016/j.jcyt.2015.02.010
• Novak, I., Walker, K., Hunt, R. W., Wallace, E. M., Fahey, M., & Badawi, N. (2016). Concise Review: Stem Cell Interventions for People With Cerebral Palsy: Systematic Review With Meta-Analysis. STEM CELLS Translational Medicine, 5(8), 1014–1025. https://doi.org/10.5966/sctm.2015-0372
• Sun, J. M., Song, A. W., Case, L. E., Mikati, M. A., Gustafson, K. E., Simmons, R., … Kurtzberg, J. (2017). Effect of Autologous Cord Blood Infusion on Motor Function and Brain Connectivity in Young Children with Cerebral Palsy: A Randomized, Placebo-Controlled Trial. Stem Cells Translational Medicine, 6(12), 2071–2078. https://doi.org/10.1002/sctm.17-0102
• Huang, L., Zhang, C., Gu, J., Wu, W., Shen, Z., Zhou, X., & Lu, H. (2018). A Randomized, Placebo-Controlled Trial of Human Umbilical Cord Blood Mesenchymal Stem Cell Infusion for Children With Cerebral Palsy. Cell Transplantation, 27(2), 325–334. https://doi.org/10.1177/0963689717729379

Sources For Systematic Reviews:

• Toyserkani, N. M., Jørgensen, M. G., Tabatabaeifar, S., Jensen, C. H., Sheikh, S. P., & Sørensen, J. A. (2017). Concise Review: A Safety Assessment of Adipose-Derived Cell Therapy in Clinical Trials: A Systematic Review of Reported Adverse Events. Stem Cells Translational Medicine, 6(9), 1786–1794. https://doi.org/10.1002/sctm.17-0031
• Can, A., Celikkan, F. T., & Cinar, O. (2017). Umbilical cord mesenchymal stromal cell transplantations: A systemic analysis of clinical trials. Cytotherapy, 19(12), 1351–1382. https://doi.org/10.1016/j.jcyt.2017.08.004