title: Repair of Torn Avascular Meniscal Cartilage Using Undifferentiated Autologous Mesenchymal Stem Cells: From In Vitro Optimization to a First-in-Human Study.
abstract: Meniscal cartilage tears are common and predispose to osteoarthritis (OA). Most occur in the avascular portion of the meniscus where current repair techniques usually fail. We described previously the use of undifferentiated autologous mesenchymal stem cells (MSCs) seeded onto a collagen scaffold (MSC/collagen-scaffold) to integrate meniscal tissues in vitro. Our objective was to translate this method into a cell therapy for patients with torn meniscus, with the long-term goal of delaying or preventing the onset of OA. After in vitro optimization, we tested an ovine-MSC/collagen-scaffold in a sheep meniscal cartilage tear model with promising results after 13 weeks, although repair was not sustained over 6 months. We then conducted a single center, prospective, open-label first-in-human safety study of patients with an avascular meniscal tear. Autologous MSCs were isolated from an iliac crest bone marrow biopsy, expanded and seeded into the collagen scaffold. The resulting human-MSC/collagen-scaffold implant was placed into the meniscal tear prior to repair with vertical mattress sutures and the patients were followed for 2 years. Five patients were treated and there was significant clinical improvement on repeated measures analysis. Three were asymptomatic at 24 months with no magnetic resonance imaging evidence of recurrent tear and clinical improvement in knee function scores. Two required subsequent meniscectomy due to retear or nonhealing of the meniscal tear at approximately 15 months after implantation. No other adverse events occurred. We conclude that undifferentiated MSCs could provide a safe way to augment avascular meniscal repair in some patients. Registration: EU Clinical Trials Register, 2010-024162-22. Stem Cells Translational Medicine 2017;6:1237-1248.
authors.affiliation: Musculoskeletal Research Unit, School of Clinical Sciences.|Avon Orthopaedic Centre, Southmead Hospital, North Bristol NHS Trust, Bristol, United Kingdom.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Whitehouse
authors.affiliation: Musculoskeletal Research Unit, School of Clinical Sciences.|Avon Orthopaedic Centre, Southmead Hospital, North Bristol NHS Trust, Bristol, United Kingdom.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Howells
authors.affiliation: Musculoskeletal Research Unit, School of Clinical Sciences.|Orthopaedic Oncology Unit, Royal Orthopaedic Hospital, Birmingham, United Kingdom.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Parry
authors.affiliation: CMT Laboratory, NHS Blood and Transplant, Speke, Liverpool, United Kingdom.
authors.forename: Eric
authors.initials: E
authors.lastname: Austin
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Wael
authors.initials: W
authors.lastname: Kafienah
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Kyla
authors.initials: K
authors.lastname: Brady
authors.affiliation: Institute of Orthopaedics, University College London, United Kingdom.
authors.forename: Allen E
authors.initials: AE
authors.lastname: Goodship
authors.affiliation: Avon Orthopaedic Centre, Southmead Hospital, North Bristol NHS Trust, Bristol, United Kingdom.|Department of Orthopaedics, Bristol Royal Infirmary, University Hospitals Bristol, Bristol, United Kingdom.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Eldridge
authors.affiliation: Musculoskeletal Research Unit, School of Clinical Sciences.|Avon Orthopaedic Centre, Southmead Hospital, North Bristol NHS Trust, Bristol, United Kingdom.
authors.forename: Ashley W
authors.initials: AW
authors.lastname: Blom
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.|Azellon Ltd, London, United Kingdom.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Hollander
mesh_terms: D000818:Animals; D002357:Cartilage Diseases / Q000628:therapy*; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008592:Menisci, Tibial / Q000166:cytology; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology*; D012756:Sheep; D000070600:Tibial Meniscus Injuries / Q000628:therapy*; D023822:Tissue Engineering / Q000379:methods; D054457:Tissue Scaffolds; D014945:Wound Healing / Q000502:physiology
keywords: Cell therapy; Meniscal cartilage; Mesenchymal stem cells; Tissue engineering