Across 55 randomized trials with 2,696 patients, the 2020 update of the intravascular mesenchymal stromal cell safety meta-analysis found one excess event, transient fever, and no increase in infection, thrombotic or embolic events, death or malignancy [1]. The serious harms on record, including blindness, bloodstream infections and a spinal mass, came from unregulated clinics using specific routes and products that had not been tested, and the FDA has documented them in its consumer pages [6, 7, 10].
Four questions follow from that record: what the pooled trial data report, which harms have been documented and under what conditions, which questions the evidence has not yet answered, and what release testing on a documented lot of mesenchymal stem cells shows. It is written for practitioners weighing a cell-based product and for patients who want the sources behind the headlines. ExaVeyra Sciences supplies mesenchymal stem cells from an FDA-registered tissue bank, and every clinical decision described here belongs to the practitioner.
Regulatory status
The FDA states in its consumer alert that stem cell products generally require FDA approval, and that the approved stem cell products consist of blood-forming stem cells derived from umbilical cord blood, approved for disorders of blood production [9]; its current approved-products list also includes OMISIRGE and several gene-modified hematopoietic stem cell products [11]. In December 2024 the agency approved the first mesenchymal stromal cell product, an allogeneic bone marrow derived product for a pediatric transplant complication [11]. Most other MSC products are section 351 biologics that reach a patient through a biologics license or an investigational new drug application [22]. ExaVeyra supplies mesenchymal stem cells from an FDA-registered tissue bank to practices in states whose laws permit it, with the 351 biologic status applying everywhere, and the practitioner and their counsel decide whether and how any product is used.
Pooled trial data place transient fever as the one consistent adverse event
Thompson and colleagues pooled 55 randomized trials that compared intravenous or intra-arterial MSCs with controls in 2,696 adults and reported in 2020 that fever was more frequent with MSCs, with a relative risk of 2.48 [1]. Non-fever infusional toxicity, infection, thrombotic or embolic events, death and malignancy showed no increase, and no included trial was stopped early for safety [1].
The 2012 SafeCell review by Lalu and colleagues reached the same finding from 36 earlier studies with 1,012 participants, of which eight randomized trials enrolled 321 [2]. The meta-analysis of those trials detected an association with transient fever only, and none with acute infusional toxicity, organ system complications, infection, death or malignancy [2].
For the intra-articular route, where most human data outside transplantation exist, Wiggers and colleagues reviewed 14 randomized trials of autologous MSCs in 408 knee osteoarthritis patients in 2021 and reported no serious adverse events during a maximum of 4 years of follow-up [3]. Iijima and colleagues pooled 35 studies with 2,385 patients in 2018 and reported minor events, knee pain or swelling, at a prevalence that ranged from 2 to 60 percent across studies, with no severe events [4].
Both knee reviews grade the certainty of their own evidence as low to very low, with 10 of 14 trials in the 2021 review at high risk of bias [3, 4]. On the reviews’ own grading, the safety findings are consistent across the registered trials while the efficacy evidence remains of low certainty [3, 4].
Documented serious harms trace to specific routes, products and settings
Bauer and colleagues reviewed the published case reports, clinical reports and media accounts of adverse events after unproven stem cell interventions in 2018 and described how the serious events cluster in settings outside regulated trials [5]. The table reads the best documented of those reports with the route, the product and the setting named, because each of those three variables is a question a practitioner or a patient can ask about a specific product.
| Report | Route and product | Setting | Outcome documented |
|---|---|---|---|
| Kuriyan 2017, NEJM [6] | Bilateral intravitreal injection of autologous adipose-derived cells | One US clinic | Three patients; acuity fell from 20/30 to 20/200 before to 20/200 to no light perception at one year |
| Perkins 2018, CDC MMWR [7] | Injection or infusion of a cord blood derived product contaminated before distribution | Outpatient and orthopedic clinics in Texas, Florida and Arizona | 12 patients hospitalized with bloodstream infections, joint infections or epidural abscesses; none died |
| Berkowitz 2016, NEJM [20] | Intrathecal infusions of cells | Commercial clinics in three countries | A glioproliferative lesion of the spinal cord |
| Jung 2013, Yonsei Med J [19] | Repeated intravenous infusions of autologous adipose-derived cells | Commercial provider, three family members | Multiple pulmonary emboli and infarcts on CT, with spontaneous resolution on follow-up |
The three patients in the Kuriyan series had visual acuity of 20/30 to 20/200 before the injections and 20/200 to no light perception one year later, with ocular hypertension, hemorrhage, retinal detachment or lens dislocation documented in between [6]. In the CDC investigation, unopened vials from the clinics grew the same organisms found in the patients, and the initial investigation placed the contamination before distribution [7].
The CDC report also states that although the processor and the distributor were registered with FDA, such registration is not a form of FDA approval [7]. That sentence is the reason a documented lot carries a sterility result and a donor serology panel, read against the federal regulations described below, rather than a registration number alone [23, 24].
Long-term human data have not shown tumor formation from MSC products
The FDA lists tumor formation, and cells moving to another part of the body and turning into an unintended type of tissue, among the safety concerns it has received reports of after unapproved products [10]. The mechanistic basis is real: Jeong and colleagues reported in 2011 that conventionally cultured mouse bone marrow MSCs at passage 4 carried chromosomal aberrations and formed malignant sarcomas in 30 percent of hearts and 46 percent of hindlimbs within 4 to 8 weeks [15].
Human data point the other way so far. Von Bahr and colleagues examined autopsy material from 18 patients who had received HLA-mismatched MSCs and 108 tissue samples by PCR, and reported in 2012 no ectopic tissue formation and no malignant tumors of donor origin, with donor DNA found at 1 in 100 to below 1 in 1,000 in eight patients and falling with time since infusion [13].
Hernigou and colleagues followed 1,873 patients who had received autologous bone marrow concentrate for orthopedic lesions for a mean of 12.5 years and reported in 2013 no tumor at any application site on 7,306 MRI scans and 52,430 radiographs, with 53 cancers elsewhere against 97 to 108 expected [14]. Those were minimally processed autologous cells, so the finding does not transfer directly to culture-expanded allogeneic products [14].
The European regulators and investigators convened by Barkholt and colleagues concluded in 2013 that the transformation risk is managed through quality controls on the expanded product, including genetic stability and passage number [16]. Those are items a documented lot record can show, and they are the reason the passage number appears on a characterization panel.
Intravenous use raises distinct questions on embolism and blood compatibility
Sanchez-Diaz and colleagues reviewed 109 biodistribution studies in 2021 and reported that the intravenous route leads to an initial accumulation of MSCs in the lungs with later redistribution to liver, spleen and kidneys, while intra-articular, intramuscular and intradermal routes lack systemic biodistribution [12]. Eggenhofer and colleagues found viable donor MSCs in mouse lungs for up to 24 hours after infusion and in no other organ at any time point [21].
Moll and colleagues reported in 2012 that culture-expanded MSCs carry tissue factor on their surface and trigger the instant blood-mediated inflammatory reaction after blood exposure, in proportion to cell number, donor and especially passage number [17]. In 2019 the same group noted that the infusion safety record comes from bone marrow MSCs and that products from adipose and perinatal tissue display varying levels of tissue factor, so hemocompatibility is a product-specific test [18].
The pulmonary embolism case series by Jung and colleagues, three family members after repeated intravenous infusions of autologous adipose-derived cells, is the clinical correlate of that laboratory finding [19]. Set against it, the 2020 meta-analysis found no excess of thrombotic or embolic events across 55 randomized trials, which used characterized products at defined cell numbers [1].
Understanding what the evidence does not yet show
The pooled trials report on acute safety for characterized products in registered trials [1, 2]. Several questions remain open, and a documented lot record addresses some of them while others wait on longer studies.
- Whether the infusion safety record from bone marrow MSCs transfers to products from adipose and perinatal tissue, which carry different levels of tissue factor [18]
- Long-term outcomes beyond 4 years for intra-articular use and beyond the follow-up of the autopsy and orthopedic cohorts for other routes [3, 13, 14]
- The immune response to repeated allogeneic exposure, which the trial data report as rare but which depends on HLA mismatch, cell number and route [1, 17]
- Whether the minor event rate of 2 to 60 percent after intra-articular injection reflects the cells, the procedure or the reporting standard of each study [4]
- How post-thaw viability and passage number at the point of use change the safety profile, since most products are shipped frozen [16, 25]
- Any safety statement for products that have not been characterized, since the reports of serious harm concern exactly those products [5, 7]
Reports of injury concentrate in the direct-to-consumer marketplace
Turner surveyed the US market in March 2021 and reported 1,480 businesses operating 2,754 clinics selling stem cell products that are not FDA approved, more than four times the number found five years earlier [8]. The FDA states that many patients may be misled by information about products that are illegally marketed, have not been shown to be safe or effective and in some cases may have significant safety issues [9].
The inclusion of a product in the clinicaltrials.gov database or the fact that a firm has registered with FDA and listed its product does not mean the product is legally marketed.
That sentence comes from the FDA patient information page of 2021, which also states that the agency has repeatedly notified manufacturers, clinics and practitioners of the need for investigational new drug applications to legally give these products to patients [10]. The harm reports in the table share a feature: in each case the product, the route or the setting was outside the framework the trial data describe [6, 7, 19, 20].
Any adverse event after a cell-based product can be reported to MedWatch, the FDA safety reporting program for health professionals, patients and consumers, which receives reports on biologics including human cells and tissue transplants [27]. The consumer alert also invites questions by phone and email before a person agrees to any regenerative medicine product [9].
Release testing on a documented lot answers the questions the harm reports raise
Each item in the harm reports maps to a test on a release record. The FDA guidance on chemistry, manufacturing and control for somatic cell products sets out the final product testing headings: sterility, mycoplasma and adventitious agents, identity, purity including endotoxin, potency and viability, with a minimum viability specification generally set at 70 percent [25].
| Test on the lot record | What it shows | Standard it is read against |
|---|---|---|
| Sterility | No viable bacterial or fungal contamination in the final container, the finding missing from the 2018 contaminated products [7] | 21 CFR 610.12: each lot tested by a validated method with written acceptance criteria [23] |
| Endotoxin | Bacterial endotoxin below a stated limit, reported as a measured value against the stated limit | CMC guidance, purity heading [25] |
| Mycoplasma | Absence of mycoplasma contamination from culture | CMC guidance, microbiological testing heading [25] |
| Viability | Percentage of live cells, with the assay method named; generally at least 70 percent | CMC guidance [25] |
| Identity | Expression of CD105, CD73 and CD90; absence of CD45, CD34, CD14 or CD11b, CD79alpha or CD19 and HLA-DR | ISCT minimal criteria [26] |
| Donor serology | HIV-1 and HIV-2, hepatitis B, hepatitis C and syphilis for every donor; HTLV-I and II and CMV for viable leukocyte-rich tissue | 21 CFR 1271.85 [24] |
ExaVeyra supplies mesenchymal stem cells from an FDA-registered tissue bank that ships to all 50 states and Puerto Rico, each vial carries its lot number, and a certificate of analysis exists for every lot, with serology. The certificate, the characterization panel and the cold-chain records are available on request, so a practitioner can read a lot against the table above before anything is thawed.
State law adds a second layer. Florida, Georgia, Tennessee, Nevada and Utah have enacted permission statutes with conditions such as supplier accreditation, written notice and consent, while Texas and North Carolina make selling adult stem cells for investigational use a crime, and the state guides on this site set out each statute with its primary source. The 351 biologic status applies in every state, and which products a practice may use under its own state law is a determination for the practitioner and their counsel [22].
A verified account places the lot record in the practitioner’s hands
The route forward for a practice is a verified account. Anyone may apply or ask the scientific team a question without an NPI, and NPI verification, which takes 1 to 3 business days, gives access to the practitioner portal, product documentation and pricing. From the portal a practice can request the certificate of analysis, the characterization panel and the cold-chain records for any lot before ordering.
Patients reading this can ask a practice for the same documents, and the FDA consumer alert invites them to call or email the agency with questions about any product they are offered [9]. A practice that can show a lot record against the table above can answer the documentation questions the harm reports raise, and the registered trial literature [1, 2] gives it a published reference point for the rest of its file.
Educational Disclaimer: This article is for educational purposes only and does not constitute medical or legal advice. It does not identify any material, compound, device setting or protocol as safe, effective or appropriate for any patient, and it is not intended to diagnose, treat, cure, or prevent any disease. Questions about a treatment belong with the reader’s own licensed provider. Exosome material is supplied for topical aesthetic use by licensed practitioners. No exosome product is FDA-approved for any use, and ExaVeyra Sciences makes no statement about administration, route, or outcome. Compounded medications are not FDA-approved. They are prepared by a 503A compounding pharmacy licensed by the Texas State Board of Pharmacy for an individual patient against that patient’s prescription, and are available to NPI-verified licensed practitioners only, in the states where the pharmacy is licensed. Product, device and brand names mentioned are trademarks of their respective owners and are used only to identify the products discussed. Their mention is not an endorsement, and those owners have not reviewed or endorsed this article. ExaVeyra Sciences is a supplier and takes no part in any diagnosis, treatment decision, or plan of care. Findings described are attributed to the peer-reviewed literature, trial registries and agencies cited. The content of these guides is provided for general informational purposes only. It does not constitute legal, medical, or regulatory advice, and does not establish that any particular product or practice is compliant. Regulatory requirements vary by state and depend on the circumstances of each practice. Each practitioner should consult their own legal counsel and the applicable state licensing boards before acting on anything stated here.
References
- 1.Thompson M, Mei SHJ, Wolfe D, Champagne J, Fergusson D, Stewart DJ, et al. Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: An updated systematic review and meta-analysis. EClinicalMedicine. 2020;19:100249. PMID 31989101. doi:10.1016/j.eclinm.2019.100249Systematic review and random-effects meta-analysis of randomized controlled trials comparing intravascular MSCs with controls in adults, searches to May 2018; 55 trials, 2,696 patients. Carries in this article: fever was more frequent with MSCs (relative risk 2.48, 95 percent CI 1.27 to 4.86), with no increase in non-fever infusional toxicity, infection, thrombotic or embolic events, death or malignancy, and no trial stopped early for safety. Funding: Stem Cell Network, Ontario Institute for Regenerative Medicine and Ontario Research Fund; two authors report affiliations with Northern Therapeutics.
- 2.Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One. 2012;7(10):e47559. PMID 23133515. doi:10.1371/journal.pone.0047559Systematic review of prospective trials using intravenous or intra-arterial MSCs, searches to June 2011; 36 studies, 1,012 participants, of which 8 randomized trials enrolled 321. Carries in this article: the meta-analysis of the randomized trials detected an association with transient fever only, and none with acute infusional toxicity, organ system complications, infection, death or malignancy. Disclosure: one author was president and CEO of Northern Therapeutics.
- 3.Wiggers TG, Winters M, Van den Boom NA, Haisma HJ, Moen MH. Autologous stem cell therapy in knee osteoarthritis: a systematic review of randomised controlled trials. Br J Sports Med. 2021;55(20):1161-1169. PMID 34039582. doi:10.1136/bjsports-2020-103671Systematic review of randomized controlled trials of autologous MSCs from bone marrow, adipose tissue or activated peripheral blood in knee osteoarthritis, searches to December 2020, with ROB 2 and GRADE; 14 trials, 408 patients. Carries in this article: no serious adverse events were reported during a maximum of 4 years of follow-up, 10 of 14 trials were at high risk of bias, and certainty was low to very low. Disclosure: competing interests none declared.
- 4.Iijima H, Isho T, Kuroki H, Takahashi M, Aoyama T. Effectiveness of mesenchymal stem cells for treating patients with knee osteoarthritis: a meta-analysis toward the establishment of effective regenerative rehabilitation. NPJ Regen Med. 2018;3:15. PMID 30245848. doi:10.1038/s41536-018-0041-8Systematic review with meta-analysis of intra-articular injection or arthroscopic implantation of MSCs in knee osteoarthritis; 35 studies, 2,385 patients. Carries in this article: minor adverse events (knee pain or swelling) were reported with a prevalence that ranged from 2 to 60 percent across studies, no severe adverse events occurred, and GRADE certainty was very low to low. Disclosure: no competing financial interests.
- 5.Bauer G, Elsallab M, Abou-El-Enein M. Concise Review: A Comprehensive Analysis of Reported Adverse Events in Patients Receiving Unproven Stem Cell-Based Interventions. Stem Cells Transl Med. 2018;7(9):676-685. PMID 30063299. doi:10.1002/sctm.17-0282Review of scientific publications, clinical case reports and mass media reports of safety incidents after unproven stem cell interventions, with an analysis of the factors behind the growth of stem cell tourism. Carries in this article: the reported serious events cluster in settings outside regulated trials, and the review is the index of case reports that the table in this article draws on. Disclosure: none stated in the PubMed record.
- 6.Kuriyan AE, Albini TA, Townsend JH, Rodriguez M, Pandya HK, Leonard RE 2nd, et al. Vision Loss after Intravitreal Injection of Autologous "Stem Cells" for AMD. N Engl J Med. 2017;376(11):1047-1053. PMID 28296617. doi:10.1056/NEJMoa1609583Case series of three patients evaluated at academic eye institutes after bilateral intravitreal injection of autologous adipose-derived cells at one US clinic. Carries in this article: visual acuity before the injections ranged from 20/30 to 20/200, the loss was associated with ocular hypertension, hemorrhagic retinopathy, vitreous hemorrhage, retinal detachment or lens dislocation, and at one year acuity ranged from 20/200 to no light perception. Disclosure: none stated in the PubMed record.
- 7.Perkins KM, Spoto S, Rankin DA, Dotson NQ, Malarkey M, Mendoza M, et al. Notes from the Field: Infections After Receipt of Bacterially Contaminated Umbilical Cord Blood-Derived Stem Cell Products for Other Than Hematopoietic or Immunologic Reconstitution - United States, 2018. MMWR Morb Mortal Wkly Rep. 2018;67(50):1397-1399. PMID 30571672. doi:10.15585/mmwr.mm6750a5. Verified 4 November 2026 at https://www.cdc.gov/mmwr/volumes/67/wr/mm6750a5.htmCDC field report of a multistate investigation with FDA and state health departments. Carries in this article: 12 patients in Texas, Florida and Arizona were hospitalized with bloodstream infections, joint infections or epidural abscesses after injections or infusions of a cord blood derived product, unopened vials grew the same organisms, the initial investigation placed the contamination before distribution, and the report states that FDA registration is not a form of FDA approval. Disclosure: no potential conflicts reported.
- 8.Turner L. The American stem cell sell in 2021: U.S. businesses selling unlicensed and unproven stem cell interventions. Cell Stem Cell. 2021;28(11):1891-1895. PMID 34739831. doi:10.1016/j.stem.2021.10.008Systematic internet survey of US businesses marketing stem cell interventions, conducted in March 2021. Carries in this article: 1,480 businesses operating 2,754 clinics were selling stem cell products that are not FDA approved, more than four times the number found in the 2016 survey by the same author. Disclosure: none stated in the PubMed record.
- 9.U.S. Food and Drug Administration. Consumer Alert on Regenerative Medicine Products Including Stem Cells and Exosomes. Dated July 22, 2020; content current as of April 9, 2024; verified 4 November 2026. https://www.fda.gov/vaccines-blood-biologics/consumers-biologics/consumer-alert-regenerative-medicine-products-including-stem-cells-and-exosomesAgency consumer page. Carries in this article: stem cell products are regulated by FDA and generally require FDA approval; the approved stem cell products consist of blood-forming stem cells derived from umbilical cord blood, approved for disorders of blood production; there are no FDA-approved exosome products; adverse events should be reported to MedWatch; and the agency invites questions by phone and email before a person agrees to any regenerative medicine product.
- 10.U.S. Food and Drug Administration. Important Patient and Consumer Information About Regenerative Medicine Therapies. Dated June 3, 2021; verified 4 November 2026. https://www.fda.gov/vaccines-blood-biologics/consumers-biologics/important-patient-and-consumer-information-about-regenerative-medicine-therapiesAgency consumer page. Carries in this article: the FDA states it has received reports of blindness, tumor formation, infections and more after use of unapproved products; the listed safety concerns include neurological events, bacterial infections including life-threatening blood infections, reactions at the collection and administration sites, unwanted inflammatory or immune response, cells moving elsewhere and forming unintended tissue or a tumor, and cross-contamination; and inclusion in clinicaltrials.gov or FDA registration does not mean a product is legally marketed.
- 11.U.S. Food and Drug Administration. FDA Approves First Mesenchymal Stromal Cell Therapy to Treat Steroid-refractory Acute Graft-versus-host Disease. Press release, December 18, 2024; verified 4 November 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-mesenchymal-stromal-cell-therapy-treat-steroid-refractory-acute-graft-versus-host. Listed on Approved Cellular and Gene Therapy Products, content current as of October 30, 2026. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-productsAgency press release and the licensed product list. Carries in this article: Ryoncil (remestemcel-L-rknd), an allogeneic bone marrow derived MSC product, was approved on December 18, 2024 for pediatric patients aged two months and older with steroid-refractory acute graft-versus-host disease, as the first FDA-approved MSC product; the release states that infusion should be monitored by the treating physician and discontinued on evidence of a reaction such as dyspnea, hypotension, fever or tachypnea.
- 12.Sanchez-Diaz M, Quiñones-Vico MI, Sanabria de la Torre R, Montero-Vílchez T, Sierra-Sánchez A, Molina-Leyva A, et al. Biodistribution of Mesenchymal Stromal Cells after Administration in Animal Models and Humans: A Systematic Review. J Clin Med. 2021;10(13):2925. PMID 34210026. doi:10.3390/jcm10132925Systematic review of biodistribution studies after intravenous, intra-arterial, intramuscular, intra-articular and intralesional routes; 109 articles. Carries in this article: the intravenous route leads to an initial accumulation in the lungs with later redistribution to liver, spleen and kidneys, the intra-arterial route bypasses the lungs, and intramuscular, intra-articular and intradermal routes lack systemic biodistribution. Disclosure: no conflict of interest declared.
- 13.von Bahr L, Batsis I, Moll G, Hägg M, Szakos A, Sundberg B, et al. Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells. 2012;30(7):1575-1578. PMID 22553154. doi:10.1002/stem.1118Autopsy study of 18 patients who had received HLA-mismatched MSCs, with 108 tissue samples from 15 patients examined by PCR. Carries in this article: no ectopic tissue formation and no malignant tumors of MSC donor origin were found, donor DNA was detected at levels of 1 in 100 to below 1 in 1,000 in eight patients, and detection fell with time since infusion (9 of 13 infusions within 50 days, 2 of 8 given earlier). Disclosure: none stated in the PubMed record.
- 14.Hernigou P, Homma Y, Flouzat-Lachaniette CH, Poignard A, Chevallier N, Rouard H. Cancer risk is not increased in patients treated for orthopaedic diseases with autologous bone marrow cell concentrate. J Bone Joint Surg Am. 2013;95(24):2215-2221. PMID 24352775. doi:10.2106/JBJS.M.00261Long-term cohort of 1,873 patients who received autologous bone marrow concentrate for orthopedic lesions between 1990 and 2006, mean follow-up 12.5 years (range 5 to 22). Carries in this article: no tumor was found at the application sites on 7,306 MRI scans and 52,430 radiographs, 53 cancers elsewhere compared with 97 to 108 expected, and a standardized incidence ratio of 0.49 to 0.54. Autologous, minimally processed cells, so the finding does not transfer directly to culture-expanded allogeneic products. Disclosure: none stated in the PubMed record.
- 15.Jeong JO, Han JW, Kim JM, Cho HJ, Park C, Lee N, et al. Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy. Circ Res. 2011;108(11):1340-1347. PMID 21493893. doi:10.1161/CIRCRESAHA.110.239848Mouse study of conventionally cultured bone marrow MSCs at passage 4. Carries in this article: growing tumors were observed in 30 percent of hearts and 46 percent of hindlimbs at 4 to 8 weeks, histology showed malignant sarcoma, and the cells carried multiple chromosomal aberrations, the reason the authors recommend chromosomal monitoring of expanded cells. Mouse cells, which transform in culture far more readily than human MSCs. Funding: NIH and non-US government support.
- 16.Barkholt L, Flory E, Jekerle V, Lucas-Samuel S, Ahnert P, Bisset L, et al. Risk of tumorigenicity in mesenchymal stromal cell-based therapies--bridging scientific observations and regulatory viewpoints. Cytotherapy. 2013;15(7):753-759. PMID 23602595. doi:10.1016/j.jcyt.2013.03.005Report of a meeting convened by the European Medicines Agency Cell Products Working Party and Committee for Advanced Therapies with European MSC experts. Carries in this article: the regulatory reading of transformation potential, with the quality, nonclinical and clinical expectations that follow, which is why genetic stability and passage number appear on a documented lot record. Disclosure: authors include regulators and academic investigators; no funding statement in the PubMed record.
- 17.Moll G, Rasmusson-Duprez I, von Bahr L, Connolly-Andersen AM, Elgue G, Funke L, et al. Are therapeutic human mesenchymal stromal cells compatible with human blood? Stem Cells. 2012;30(7):1565-1574. PMID 22522999. doi:10.1002/stem.1111Laboratory and patient study of the instant blood-mediated inflammatory reaction (IBMIR) triggered by culture-expanded MSCs. Carries in this article: MSCs carry tissue factor on their surface and triggered IBMIR after blood exposure in proportion to cell number, donor and especially passage number, and patients infused with low-passage cells at 1 to 3 million cells per kilogram showed blood activation markers without D-dimer or acute-phase reactants. Funding: non-US government and US Public Health Service support.
- 18.Moll G, Ankrum JA, Kamhieh-Milz J, Bieback K, Ringdén O, Volk HD, et al. Intravascular Mesenchymal Stromal/Stem Cell Therapy Product Diversification: Time for New Clinical Guidelines. Trends Mol Med. 2019;25(2):149-163. PMID 30711482. doi:10.1016/j.molmed.2018.12.006Narrative review. Carries in this article: meta-analysis has shown bone marrow MSC infusion to be safe, it is not established that the same holds for products from adipose and perinatal tissue, and different MSC products display varying levels of procoagulant tissue factor, which is why hemocompatibility testing belongs on an intravascular product. Disclosure: non-US government research support listed in the PubMed record.
- 19.Jung JW, Kwon M, Choi JC, Shin JW, Park IW, Choi BW, et al. Familial occurrence of pulmonary embolism after intravenous, adipose tissue-derived stem cell therapy. Yonsei Med J. 2013;54(5):1293-1296. PMID 23918585. doi:10.3349/ymj.2013.54.5.1293Case report of three family members. Carries in this article: a 41-year-old man and his parents developed multiple pulmonary emboli and infarcts on CT after repeated intravenous infusions of autologous adipose-derived cells (three and five courses respectively), with spontaneous resolution on follow-up imaging. Disclosure: no financial conflicts of interest.
- 20.Berkowitz AL, Miller MB, Mir SA, Cagney D, Chavakula V, Guleria I, et al. Glioproliferative Lesion of the Spinal Cord as a Complication of "Stem-Cell Tourism". N Engl J Med. 2016;375(2):196-198. PMID 27331440. doi:10.1056/NEJMc1600188Case report from an academic neurosurgical service. Carries in this article: a glioproliferative lesion of the spinal cord in a man who had received intrathecal infusions of cells at commercial clinics in three countries, one of the few documented cases of a mass of donor cell origin after an unregulated procedure. Disclosure: none stated in the PubMed record.
- 21.Eggenhofer E, Benseler V, Kroemer A, Popp FC, Geissler EK, Schlitt HJ, et al. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol. 2012;3:297. PMID 23056000. doi:10.3389/fimmu.2012.00297Mouse tracking study of 500,000 labeled MSCs infused by tail vein. Carries in this article: viable donor MSCs were present in the lungs up to 24 hours and then disappeared, no viable MSCs were found in liver, spleen, kidney or bone marrow at any time point, and the authors conclude that long-term effects must be mediated by other cell types. Disclosure: none stated in the PubMed record.
- 22.U.S. Food and Drug Administration. 21 CFR 1271.10, Are my HCT/Ps regulated solely under section 361 of the PHS Act and the regulations in this part, and if so what must I do? (66 FR 5466, 2001, as amended 2004; text verified on eCFR 4 November 2026). https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=1271.10 and https://www.ecfr.gov/current/title-21/chapter-I/subchapter-L/part-1271/subpart-A/section-1271.10Federal regulation. Carries in this article: the four cumulative criteria (minimal manipulation, homologous use as reflected by labeling and advertising, no combination with another article beyond water, crystalloids or a sterilizing, preserving or storage agent, and no systemic effect or dependence on living cells unless autologous, close-relative or reproductive) that place a product under section 361 alone, and the registration and listing duty for establishments that make such products.
- 23.U.S. Food and Drug Administration. 21 CFR 610.12, Sterility (text verified on eCFR 4 November 2026). https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=610.12 and https://www.ecfr.gov/current/title-21/chapter-I/subchapter-F/part-610/subpart-B/section-610.12Federal regulation for licensed biological products. Carries in this article: manufacturers must perform sterility testing of each lot of final container material, the test must be validated to reliably detect viable contaminating microorganisms, and written procedures must state the method, the sampling plan and the acceptance and rejection specifications for each lot. Cited as the standard a lot-specific sterility result is read against.
- 24.U.S. Food and Drug Administration. 21 CFR 1271.85, What donor testing is required for different types of cells and tissues? (text verified on eCFR 4 November 2026). https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=1271.85 and https://www.ecfr.gov/current/title-21/chapter-I/subchapter-L/part-1271/subpart-C/section-1271.85Federal regulation, donor eligibility. Carries in this article: a specimen from every donor of cells or tissue must be tested for HIV types 1 and 2, hepatitis B virus, hepatitis C virus and Treponema pallidum, and donors of viable, leukocyte-rich cells or tissue must also be tested for HTLV types I and II and for cytomegalovirus, the serology that appears on a lot record.
- 25.U.S. Food and Drug Administration, Center for Biologics Evaluation and Research. Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs). Guidance for FDA Reviewers and Sponsors, April 2008, docket FDA-2008-D-0206; page and PDF verified 4 November 2026. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/content-and-review-chemistry-manufacturing-and-control-cmc-information-human-somatic-cell-therapy and https://www.fda.gov/media/73624/downloadAgency guidance. Carries in this article: the final product testing headings for a cell product, which are microbiological testing (sterility, mycoplasma and adventitious agents), identity, purity (residual contaminants and pyrogenicity or endotoxin), potency and viability, and the statement that for somatic cellular therapies the minimum acceptable viability specification is generally set at 70 percent.
- 26.Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-317. PMID 16923606. doi:10.1080/14653240600855905Society position statement. Carries in this article: the identity criteria an MSC lot is read against, namely plastic adherence, expression of CD105, CD73 and CD90, absence of CD45, CD34, CD14 or CD11b, CD79alpha or CD19 and HLA-DR, and differentiation to osteoblasts, adipocytes and chondroblasts in vitro.
- 27.U.S. Food and Drug Administration. MedWatch: The FDA Safety Information and Adverse Event Reporting Program. Content current as of November 3, 2026; verified 4 November 2026. https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting-programAgency reporting program page. Carries in this article: MedWatch is the FDA medical product safety reporting program for health professionals, patients and consumers, and it receives reports on biologics including human cells and tissue transplants, the route the consumer alert names for any adverse event after a regenerative medicine product.