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

Ultrasound anatomy of the normal stifle in the sheep

“…In humans, US has been reported to be a valid alternative to magnetic resonance imaging in the assessment of meniscal extrusion (Papalia et al, ). Ovine mesenchymal stem cells/collagen scaffold was tested in a sheep meniscal cartilage tear model (Whitehouse et al, ); different repair techniques have also been tested (Scotti, Hirschmann, Antinolfi, Martin, & Peretti, ) such as stem cells seeded into scaffolds, cell‐free scaffolds, gene therapy, intraarticular delivery of progenitor cells, biological glues, and partial and total tissue engineered meniscus replacement. Meniscectomy and induction of meniscal tears can be performed on medial (Gruchenberg, Burkhardt, Read, & Bellenger, ) and lateral (Beveridge, Shrive, & Frank, ) meniscus in the sheep (Little et al, ).…”

Optimal Storage Conditions for Apheresis Research (OSCAR): a Biomedical Excellence for Safer Transfusion (BEST) Collaborative study

“…These data may also help guide decision making on the optimal storage and transport conditions for future clinical trials, similar to analysis of stress variables 3 and clinical application models demonstrated in other studies. [14][15][16] While it is difficult to predict whether the variability seen in this in vitro study would have clinical consequences to patients who receive cell therapy products, suboptimal storage conditions and high variability in cell dosage should be avoided whenever possible.…”

Novel Approaches in Meniscal Repair Utilizing Mesenchymal Stem Cells, New Generation Bioscaffolds and Biological Adhesives as Cell Delivery Vehicles

“…Direct intra-synovial injections of MSCs have also been employed and meniscal regeneration and resolution of pain recorded [135,141]. MSCs sourced from a number of tissues including synovial tissues [142][143][144][145], adipose [146,147], bone marrow [45, [148][149][150]] and blood vessels [151] have been applied in a number of applications to promote meniscal repair [44-48, [152][153][154][155][156][157][158] (Table 1). Co-cultures of meniscal cells and MSCs have also been examined in meniscal repair strategies [43, 159,160].…”