Concise Review: A Safety Assessment of Adipose-Derived Cell Therapy in Clinical Trials: A Systematic Review of Reported Adverse Events

Navid Mohamadpour Toyserkani, Mads Gustaf Jørgensen, Siavosh Tabatabaeifar, Charlotte Harken Jensen, Søren Paludan Sheikh, Jens Ahm Sørensen, Navid Mohamadpour Toyserkani, Mads Gustaf Jørgensen, Siavosh Tabatabaeifar, Charlotte Harken Jensen, Søren Paludan Sheikh, Jens Ahm Sørensen

Abstract

The popularity of adipose-derived cell therapy has increased over the last decade, and the number of studies published annually is growing. However, concerns regarding safety in the setting of previous malignancy or the use of allogeneic cells have been raised. We therefore aimed to systematically review all clinical studies using adipose-derived cell therapy to identify reported adverse events with a special focus on risk of thromboembolic, immunological, and oncological safety concerns. Our systematic search resulted in 70 included studies involving more than 1,400 patients that were treated with adipose-derived cell therapy. Safety assessment method was not described in 32 of the included studies. For studies involving systemic or cardiac administration, one case of pulmonary thromboembolism and cases of both myocardial and cerebral infarctions were described. In the setting of allogeneic cell therapy studies, where the production of specific antibodies toward donor cells was examined, it was noted that 19%-34% of patients develop antibodies, but the consequence of this is unknown. With regard to oncological safety, only one case of breast cancer recurrence was identified out of 121 patients. Adipose-derived cell therapy has so far shown a favorable safety profile, but safety assessment description has, in general, been of poor quality, and only adverse events that are looked for will be found. We encourage future studies to maintain a strong focus on the safety profile of cell therapy, so its safeness can be confirmed. Stem Cells Translational Medicine 2017;6:1786-1794.

Keywords: Adipose-derived stromal cells; Adverse events; Complications; Safety; Stromal vascular fraction.

© 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Figures

Figure 1
Figure 1
Flow chart of article selection process.
Figure 2
Figure 2
An overview of included studies. (A): Graphical overview of the range of indications adipose‐derived cell therapy has been used for. (B): Graphical overview of research activity bias on geographic location showing that the majority of included studies are from either Europe or Asia. (C): The majority of studies were of case series quality with no control group for comparison. Eight of studies included a nonrandom control group and 19 studies were randomized studies. (D): Since the first publication in 2005 there has been a steady rise in research output of clinical studies using adipose‐derived cell therapy.

References

    1. Stoltz J‐F, de Isla N, Li YP et al. Stem cells and regenerative medicine: Myth or reality of the 21th century. Stem Cells Int 2015;2015:1–19.
    1. Fraser JK, Wulur I, Alfonso Z et al. Fat tissue: An underappreciated source of stem cells for biotechnology. Trends Biotechnol 2006;24:150–154.
    1. Lin C‐S, Xin Z‐C, Wang Z et al. Stem cell therapy for erectile dysfunction: A critical review. Stem Cells Dev 2012;21:343–351.
    1. van der Spoel TIG, Jansen of Lorkeers SJ, Agostoni P et al. Human relevance of pre‐clinical studies in stem cell therapy: Systematic review and meta‐analysis of large animal models of ischaemic heart disease. Cardiovasc Res 2011;91:649–658.
    1. Toyserkani NM, Quaade ML, Sørensen JA. Cell‐assisted lipotransfer: A systematic review of its efficacy. Aesthetic Plast Surg 2016;40:309–318.
    1. Toyserkani NM, Christensen ML, Sheikh SP et al. Stem cells show promising results for lymphoedema treatment:‐A literature review. J Plast Surg Hand Surg 2015;75:117–123.
    1. Toyserkani NM, Christensen ML, Sheikh SP et al. Adipose‐derived stem cells: New treatment for wound healing? Ann Plast Surg 2014;49:65–71.
    1. García‐Olmo D, García‐Arranz M, Herreros D et al. A phase I clinical trial of the treatment of Crohn's fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum 2005;48:1416–1423.
    1. Furlani D, Ugurlucan M, Ong L et al. Is the intravascular administration of mesenchymal stem cells safe? Mesenchymal stem cells and intravital microscopy. Microvasc Res 2009;77:370–376.
    1. Tatsumi K, Ohashi K, Matsubara Y et al. Tissue factor triggers procoagulation in transplanted mesenchymal stem cells leading to thromboembolism. Biochem Biophys Res Commun 2013;431:203–209.
    1. Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: Immune evasive, not immune privileged. Nat Biotechnol 2014;32:252–260.
    1. Zimmerlin L, Donnenberg AD, Rubin JP et al. Regenerative therapy and cancer: In vitro and in vivo studies of the interaction between adipose‐derived stem cells and breast cancer cells from clinical isolates. Tissue Eng Part A 2011;17:93–106.
    1. Martin‐Padura I, Gregato G, Marighetti P et al. The white adipose tissue used in lipotransfer procedures is a rich reservoir of CD34 + progenitors able to promote cancer progression. Cancer Res 2012;72:325–334.
    1. Rowan BG, Gimble JM, Sheng M et al. Human adipose tissue‐derived stromal/stem cells promote migration and early metastasis of triple negative breast cancer xenografts. PLoS One 2014;9:e89595.
    1. Liberati A, Altman DG, Tetzlaff J et al. The PRISMA statement for reporting systematic reviews and meta‐analyses of studies that evaluate health care interventions: Explanation and elaboration. PLoS Med 2009;6:e1000100.
    1. Covidence systematic review software. Veritas Health Innovation. Melbourne, Australia. Available at . Accessed January 22, 2017.
    1. Higgins JPT, Altman DG. Assessing risk of bias in included studies. In Cochrane Handbook of Systematic Reviews of Interventions. In: Julian PTH, Sally G, eds. Cochrane B. Series, The Cochrane Collaboration, 2008:187–241.
    1. Amirkhani MA, Shoae‐Hassani A, Soleimani M et al. Rejuvenation of facial skin and improvement in the dermal architecture by transplantation of autologous stromal vascular fraction: A clinical study. Bioimpacts 2016;6:149–154.
    1. Aronowitz JA, Lockhart RA, Hakakian CS et al. Clinical safety of stromal vascular fraction separation at the point of care. Ann Plast Surg 2015;75:666–671.
    1. Chang Q, Li J, Dong Z, Liu L et al. Quantitative volumetric analysis of progressive hemifacial atrophy corrected using stromal vascular fraction‐supplemented autologous fat grafts. Dermatol Surg 2013;39:1465–1473.
    1. Doi K, Tanaka S, Iida H et al. Stromal vascular fraction isolated from lipo‐aspirates using an automated processing system: Bench and bed analysis. J Tissue Eng Regen Med 2013;7:864–870.
    1. Gentile P, De Angelis B, Pasin M et al. Adipose‐derived stromal vascular fraction cells and platelet‐rich plasma: Basic and clinical evaluation for cell‐based therapies in patients with scars on the face. J Craniofac Surg 2014;25:267–272.
    1. Gentile P, Orlandi A, Scioli MG et al. A comparative translational study: The combined use of enhanced stromal vascular fraction and platelet‐rich plasma improves fat grafting maintenance in breast reconstruction. Stem Cells Transl Med 2012;1:341–351.
    1. Kølle S‐FT, Fischer‐Nielsen A, Mathiasen AB et al. Enrichment of autologous fat grafts with ex‐vivo expanded adipose tissue‐derived stem cells for graft survival: A randomised placebo‐controlled trial. Lancet 2013;382:1113–1120.
    1. Li J, Gao J, Cha P et al. Supplementing fat grafts with adipose stromal cells for cosmetic facial contouring. Dermatol Surg 2013;39:449–456.
    1. Lee SK, Kim D‐W, Dhong E‐S et al. Facial soft tissue augmentation using autologous fat mixed with stromal vascular fraction. Arch Plast Surg 2012;39:534–539.
    1. Pérez‐Cano R, Vranckx JJ, Lasso JM et al. Prospective trial of adipose‐derived regenerative cell (ADRC)‐enriched fat grafting for partial mastectomy defects: The RESTORE‐2 trial. Eur J Surg Oncol 2012;38:382–389.
    1. Peltoniemi HH, Salmi A, Miettinen S et al. Stem cell enrichment does not warrant a higher graft survival in lipofilling of the breast: A prospective comparative study. J Plast Reconstr Aesthet Surg 2013;66:1494–1503.
    1. Sterodimas A, de Faria J, Nicaretta B et al. Autologous fat transplantation versus adipose‐derived stem cell‐enriched lipografts: A study. Aesthetic Surg J 2011;31:682–693.
    1. Tanikawa DYS, Aguena M, Bueno DF et al. Fat grafts supplemented with adipose‐derived stromal cells in the rehabilitation of patients with craniofacial microsomia. Plast Reconstr Surg 2013;132:141–152.
    1. Tissiani LAL, Alonso N. A prospective and controlled clinical trial on stromal vascular fraction enriched fat grafts in secondary breast reconstruction. Stem Cells Int 2016;2016:2636454.
    1. Yoshimura K, Sato K, Aoi N et al. Cell‐assisted lipotransfer for cosmetic breast augmentation: Supportive use of adipose‐derived stem/stromal cells. Aesthetic Plast Surg 2008;32:48–55; discussion 56–57.
    1. Wang L, Luo X, Lu Y et al. Is the resorption of grafted fat reduced in cell‐assisted lipotransfer for breast augmentation? Ann Plast Surg 2014;75:128–134.
    1. Koh KS, Oh TS, Kim H et al. Clinical application of human adipose tissue‐derived mesenchymal stem cells in progressive hemifacial atrophy (Parry‐Romberg disease) with microfat grafting techniques using 3‐dimensional computed tomography and 3‐dimensional camera. Ann Plast Surg 2012;69:331–337.
    1. Rigotti G, Charles‐de‐ Sá L, Gontijo‐de‐Amorim NF et al. Expanded stem cells, stromal‐vascular fraction, and platelet‐rich plasma enriched fat: Comparing results of different facial rejuvenation approaches in a clinical trial. Aesthetic Surg J 2016;36:261–270.
    1. Cho YB, Park KJ, Yoon SN et al. Long‐term results of adipose‐derived stem cell therapy for the treatment of Crohn's fistula. Stem Cells Transl Med 2015;4:532–537.
    1. Cho YB, Lee WY, Park KJ et al. Autologous adipose tissue‐derived stem cells for the treatment of Crohn's fistula: a phase I clinical study. Cell Transplant 2013;22:279–285.
    1. de la Portilla F, Alba F, García‐Olmo D et al. Expanded allogeneic adipose‐derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn's disease: Results from a multicenter phase I/IIa clinical trial. Int J Colorectal Dis 2013;28:313–323.
    1. García‐Arranz M, Dolores Herreros M, González‐Gómez C et al. Treatment of Crohn's‐related rectovaginal fistula with allogeneic expanded‐adipose derived stem cells: A phase I‐IIa clinical trial. Stem Cells Transl Med 2016;5:1441–1446.
    1. Garcia‐Olmo D, Herreros D, Pascual I et al. Expanded adipose‐derived stem cells for the treatment of complex perianal fistula: A phase II clinical trial. Dis Colon Rectum 2009;52:79–86.
    1. Guadalajara H, Herreros D, De‐La‐Quintana P et al. Long‐term follow‐up of patients undergoing adipose‐derived adult stem cell administration to treat complex perianal fistulas. Int J Colorectal Dis 2012;27:595–600.
    1. Herreros MD, Garcia‐Arranz M, Guadalajara H et al. Autologous expanded adipose‐derived stem cells for the treatment of complex cryptoglandular perianal fistulas: A phase III randomized clinical trial (FATT 1: Fistula Advanced Therapy Trial 1) and long‐term evaluation. Dis Colon Rectum 2012;55:762–772.
    1. Mizushima T, Takahashi H, Takeyama H et al. A clinical trial of autologous adipose‐derived regenerative cell transplantation for a postoperative enterocutaneous fistula. Surg Today 2016;46:835–842.
    1. Panés J, García‐Olmo D, Van Assche G et al. Expanded allogeneic adipose‐derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: A phase 3 randomised, double‐blind controlled trial. Lancet 2016;388:1281–1290.
    1. Park KJ, Ryoo S‐B, Kim JS et al. Allogeneic adipose‐derived stem cells for the treatment of perianal fistula in Crohn's disease: A pilot clinical trial. Colorectal Dis 2016;18:468–476.
    1. Sanz‐Baro R, García‐Arranz M, Guadalajara H et al. First‐in‐human case study: Pregnancy in women with Crohn's perianal fistula treated with adipose‐derived stem cells: A safety study. Stem Cells Transl Med 2015;4:598–602.
    1. Garcia‐Olmo D, Guadalajara H, Rubio‐Perez I et al. Recurrent anal fistulae: Limited surgery supported by stem cells. World J Gastroenterol 2015;21:3330–3336.
    1. Lee WY, Park KJ, Cho YB et al. Autologous adipose tissue‐derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn's fistula. Stem Cells 2013;31:2575–2581.
    1. Castillo‐Cardiel G, López‐Echaury AC, Saucedo‐Ortiz JA et al. Bone regeneration in mandibular fractures after the application of autologous mesenchymal stem cells, a randomized clinical trial. Dent Traumatol 2016;33:38–44.
    1. Fodor PB, Paulseth SG. Adipose derived stromal cell (ADSC) injections for pain management of osteoarthritis in the human knee joint. Aesthetic Surg J 2016;36:229–236.
    1. Koh Y‐G, Kwon O‐R, Kim Y‐S et al. Comparative outcomes of open‐wedge high tibial osteotomy with platelet‐rich plasma alone or in combination with mesenchymal stem cell treatment: A prospective study. Arthroscopy 2014;30:1453–1460.
    1. Koh Y‐G, Kwon O‐R, Kim Y‐S et al. Adipose‐derived mesenchymal stem cells with microfracture versus microfracture alone: 2‐year follow‐up of a prospective randomized trial. Arthroscopy 2016;32:97–109.
    1. Jo CH, Lee YG, Shin WH et al. Intra‐articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: A proof‐of‐concept clinical trial. Stem Cells 2014;32:1254–1266.
    1. Koh Y‐G, Choi Y‐J. Infrapatellar fat pad‐derived mesenchymal stem cell therapy for knee osteoarthritis. Knee 2012;19:902–907.
    1. Lee SY, Kim W, Lim C, Chung SG. Treatment of lateral epicondylosis by using allogeneic adipose‐derived mesenchymal stem cells: A pilot study. Stem Cells 2015;33:2995–3005.
    1. Pers Y‐M, Rackwitz L, Ferreira R et al. Adipose mesenchymal stromal cell‐based therapy for severe osteoarthritis of the knee: A phase i dose‐escalation trial. Stem Cells Transl Med 2016;5:847–856.
    1. Sándor GK, Numminen J, Wolff J et al. Adipose stem cells used to reconstruct 13 cases with cranio‐maxillofacial hard‐tissue defects. Stem Cells Transl Med 2014;3:530–540.
    1. Saxer F, Scherberich A, Todorov A et al. Implantation of stromal vascular fraction progenitors at bone fracture sites: From a rat model to a first‐in‐man study. Stem Cells 2016;34:2956–2966.
    1. Scuderi N, Ceccarelli S, Onesti MG et al. Human adipose‐derived stromal cells for cell‐based therapies in the treatment of systemic sclerosis. Cell Transplant 2013;22:779–795.
    1. Onesti MG, Fioramonti P, Carella S et al. Improvement of mouth functional disability in systemic sclerosis patients over one year in a trial of fat transplantation versus adipose‐derived stromal cells. Stem Cells Int 2016;2016:2416192.
    1. Álvaro‐Gracia JM, Jover JA, García‐ Vicuña R et al. Intravenous administration of expanded allogeneic adipose‐derived mesenchymal stem cells in refractory rheumatoid arthritis (Cx611): Results of a multicentre, dose escalation, randomised, single‐blind, placebo‐controlled phase Ib/IIa clinical trial. Ann Rheum Dis 2017;76:196–202.
    1. Granel B, Daumas A, Jouve E et al. Safety, tolerability and potential efficacy of injection of autologous adipose‐derived stromal vascular fraction in the fingers of patients with systemic sclerosis: An open‐label phase I trial. Ann Rheum Dis 2015;74:2175–2182.
    1. Guillaume‐Jugnot P, Daumas A, Magalon J et al. Autologous adipose‐derived stromal vascular fraction in patients with systemic sclerosis: 12‐month follow‐up. Rheumatology 2016;55:301–306.
    1. Bura A, Planat‐Benard V, Bourin P et al. Phase I trial: The use of autologous cultured adipose‐derived stroma/stem cells to treat patients with non‐revascularizable critical limb ischemia. Cytotherapy 2014;16:245–257.
    1. Lee HC, An SG, Lee HW et al. Safety and effect of adipose tissue‐derived stem cell implantation in patients with critical limb ischemia: A pilot study. Circ J 2012;76:1750–1760.
    1. Han S‐K, Kim H‐R, Kim W‐K. The treatment of diabetic foot ulcers with uncultured, processed lipoaspirate cells: A pilot study. Wound Repair Regen 2010;18:342–348.
    1. Marino G, Moraci M, Armenia E et al. Therapy with autologous adipose‐derived regenerative cells for the care of chronic ulcer of lower limbs in patients with peripheral arterial disease. J Surg Res 2013;185:36–44.
    1. Gotoh M, Yamamoto T, Kato M et al. Regenerative treatment of male stress urinary incontinence by periurethral injection of autologous adipose‐derived regenerative cells: 1‐year outcomes in 11 patients. Int J Urol 2014;21:294–300.
    1. Kuismanen K, Sartoneva R, Haimi S et al. Autologous adipose stem cells in treatment of female stress urinary incontinence: Results of a pilot study. Stem Cells Transl Med 2014;3:936–941.
    1. Haahr MK, Jensen CH, Toyserkani NM et al. Safety and potential effect of a single intracavernous injection of autologous adipose‐derived regenerative cells in patients with erectile dysfunction following radical prostatectomy: An open‐label phase I clinical trial. EBio Med 2016;5:204–10
    1. Lander EB, Berman MH, See JR. Stromal vascular fraction combined with shock wave for the treatment of Peyronie's disease. Plast Reconstr Surgery 2016;4:e631.
    1. Choi JY, Kim T‐H, Yang JD et al. Adipose‐derived regenerative cell injection therapy for postprostatectomy incontinence: A phase i clinical study. Yonsei Med J 2016;57:1152.
    1. Comella K, Parcero J, Bansal H et al. Effects of the intramyocardial implantation of stromal vascular fraction in patients with chronic ischemic cardiomyopathy. J Transl Med 2016;14:158
    1. Houtgraaf JH, den Dekker WK, van Dalen BM et al. First experience in humans using adipose tissue‐derived regenerative cells in the treatment of patients with ST‐segment elevation myocardial infarction. J Am Coll Cardiol 2012;59:539–540.
    1. Perin EC, Sanz‐Ruiz R, Sánchez PL et al. Adipose‐derived regenerative cells in patients with ischemic cardiomyopathy: The PRECISE Trial. Am Heart J 2014;168:88–95.e2.
    1. Henry TD, Pepine CJ, Lambert CR et al. The Athena trials: Autologous adipose‐derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction. Catheter Cardiovasc Interv 2016,
    1. Ra JC, Shin IS, Kim SH et al. Safety of intravenous infusion of human adipose tissue‐derived mesenchymal stem cells in animals and humans. Stem Cells Dev 2011;20:1297–1308.
    1. Staff NP, Madigan NN, Morris J et al. Safety of intrathecal autologous adipose‐derived mesenchymal stromal cells in patients with ALS. Neurology 2016;87:2230–2234.
    1. Hur JW, Cho T‐H, Park D‐H et al. Intrathecal transplantation of autologous adipose‐derived mesenchymal stem cells for treating spinal cord injury: A human trial. J Spinal Cord Med 2016;39:655–664.
    1. Calcagni M, Zimmermann S, Scaglioni MF et al. The novel treatment of SVF‐enriched fat grafting for painful end‐neuromas of superficial radial nerve. Microsurgery 2016.
    1. Fang B, Song Y, Liao L et al. Favorable response to human adipose tissue‐derived mesenchymal stem cells in steroid‐refractory acute graft‐versus‐host disease. Transplant Proc 2007;39:3358–3362.
    1. Vanikar AV, Trivedi HL, Kumar A et al. Co‐infusion of donor adipose tissue‐derived mesenchymal and hematopoietic stem cells helps safe minimization of immunosuppression in renal transplantation ‐ single center experience. Ren Fail 2014;36:1376–1384.
    1. Fang B, Mai L, Li N et al. Favorable response of chronic refractory immune thrombocytopenic purpura to mesenchymal stem cells. Stem Cells Dev 2012;21:497–502.
    1. Zheng G, Huang L, Tong H et al. Treatment of acute respiratory distress syndrome with allogeneic adipose‐derived mesenchymal stem cells: A randomized, placebo‐controlled pilot study. Respir Res 2014;15:39.
    1. Tzouvelekis A, Paspaliaris V, Koliakos G et al. A prospective, non‐randomized, no placebo‐controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells‐stromal vascular fraction in idiopathic pulmonary fibrosis. J Transl Med 2013;11:171.
    1. Oner A, Gonen ZB, Sinim N et al. Subretinal adipose tissue‐derived mesenchymal stem cell implantation in advanced stage retinitis pigmentosa: A phase I clinical safety study. Stem Cell Res Ther 2016;7:178.
    1. Gotoh M, Yamamoto T, Kato M et al. Regenerative treatment of male stress urinary incontinence by periurethral injection of autologous adipose‐derived regenerative cells: 1‐year outcomes in 11 patients. Int J Urol 2014;21:294–300.
    1. Gimble JM, Bunnell BA, Chiu ES et al. Concise review: Adipose‐derived stromal vascular fraction cells and stem cells: Let's not get lost in translation. Stem Cells 2011;29:749–754.
    1. Waked K, Colle J, Doornaert M et al. Systematic review: The oncological safety of adipose fat transfer after breast cancer surgery. Breast 2016;31:128–136.
    1. Ioannidis JPA. Why most published research findings are false. PLoS Med 2005;2:e124.
    1. Wartolowska KA, Feakins BG, Collins GS et al. The magnitude and temporal changes of response in the placebo arm of surgical randomized controlled trials: A systematic review and meta‐analysis. Trials 2016;17:589.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera