title: Safety of intra-articular cell-therapy with culture-expanded stem cells in humans: a systematic literature review.
abstract: BACKGROUND
  An important goal of stem cell research in orthopaedics is to develop clinically relevant techniques that could be applied to heal cartilage or joint pathology. Stem cell treatment in orthopaedics for joint pathology is promising since these cells have the ability to modulate different processes in the various tissues of the joint simultaneously. The non life-threatening nature of musculoskeletal system disorders makes safety of stem cell therapy a necessary prerequisite.
  
  
  OBJECTIVE
  To systematically review the literature and provide an overview of reported adverse events (AEs) of intra-articular treatment with culture-expanded stem cells in humans.
  
  
  METHODS
  A systematic literature search was performed in Pubmed, EMBASE, Web of Science and CINAHL in February 2013. AEs were reported into three categories: local/systemic, serious adverse event or AE (SAE/AE), related/unrelated.
  
  
  RESULTS
  3039 Potentially eligible articles were identified of which eventually eight fulfilled our inclusion criteria. In total, 844 procedures with a mean follow-up of 21 months were analysed. Autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) were used for cartilage repair and osteoarthritis treatment in all included studies. Four SAEs were reported by the authors. One infection following bone marrow aspiration (BMA) was reported as probably related and resolved with antibiotics. One pulmonary embolism occurred 2 weeks after BMA and was reported as possibly related. Two tumours, both not at the site of injection, were reported as unrelated. Twenty-two other cases of possible procedure-related and seven of possible stem cell-product related adverse events (AEs) were documented. The main AEs related to the procedure were increased pain/swelling and dehydration after BMA. Increased pain and swelling was the only AE reported as related to the stem cell-product.
  
  
  CONCLUSIONS
  Based on current literature review we conclude that application of cultured stem cells in joints appears to be safe. We believe that with continuous caution for potential side effects, it is reasonable to continue with the development of articular stem cell therapies.
authors.affiliation: Department of Orthopaedics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: C M M
authors.initials: CM
authors.lastname: Peeters
authors.forename: M J C
authors.initials: MJ
authors.lastname: Leijs
authors.forename: M
authors.initials: M
authors.lastname: Reijman
authors.forename: G J V M
authors.initials: GJ
authors.lastname: van Osch
authors.forename: P K
authors.initials: PK
authors.lastname: Bos
mesh_terms: D018929:Cell Culture Techniques; D002478:Cells, Cultured / Q000637:transplantation; D006801:Humans; D007270:Injections, Intra-Articular; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects* / Q000379:methods*; D010003:Osteoarthritis / Q000628:therapy*
keywords: Culture-expanded; Humans; Intra-articular; Safety; Stem cells