Osteonecrosis of the Femoral Head Safely Healed with Autologous, Expanded, Bone Marrow-Derived Mesenchymal Stromal Cells in a Multicentric Trial with Minimum 5 Years Follow-Up

Abstract

Background: Osteonecrosis (ON) of the femoral head represents a potentially severe disease of the hip where the lack of bone regeneration may lead to femoral head collapse and secondary osteoarthritis, with serious pain and disability. The aim of this European, multicentric clinical trial was to prove safety and early efficacy to heal early femoral head ON in patients through minimally invasive surgical implantation of autologous mesenchymal stromal cells (MSC) expanded from bone marrow (BM) under good manufacturing practices (GMP). Methods: Twenty-two patients with femoral head ON (up to ARCO 2C) were recruited and surgically treated in France, Germany, Italy and Spain with BM-derived, expanded autologous MSC (total dose 140 million MSC in 7 mL). The investigational advanced therapy medicinal product (ATMP) was expanded from BM under the same protocol in all four countries and approved by each National Competent Authority. Patients were followed during two years for safety, based on adverse events, and for efficacy, based on clinical assessment (pain and hip score) and imaging (X-rays and MRIs). Patients were also reviewed after 5 to 6 years at latest follow-up for final outcome. Results: No severe adverse event was recalled as related to the ATMP. At 12 months, 16/20 per protocol and 16/22 under intention-to-treat (2 drop-out at 3 and 5 months) maintained head sphericity and showed bone regeneration. Of the 4 hips with ON progression, 3 required total hip replacement (THR). At 5 years, one patient (healed at 2 years visit) was not located, and 16/21 showed no progression or THR, 4/21 had received THR (all in the first year) and 1 had progressed one stage without THR. Conclusions: Expanded MSCs implantation was safe. Early efficacy was confirmed in 80% of cases under protocol at 2 years. At 5 years, the overall results were maintained and 19% converted to THR, all in the first year.

Implantation of autologous Expanded Mesenchymal Stromal Cells in Hip Osteonecrosis through Percutaneous Forage: Evaluation of the Operative Technique

“…Anonymized imaging from 22 patients treated for osteonecrosis of the femoral head under the Ortho 2 clinical trial (EudraCT 2012-002010-39) in the REBORNE EU-funded project (Regenerating bone defects using new biomedical engineering approaches, FP7 HEALTH-2009-1.4-2, Grant Agreement 241879) is the material under study [26]. Briefly, the trial was conducted in five clinical centers from four European countries (France, Germany, Italy and Spain) from March 2014 to June 2015.…”

“…The injected cell product consisted of a dose of 140 million MSCs suspended in 5% human albumin (20 million MSCs/mL). Cell expansion details have been published elsewhere [26,32]. Each patient underwent repeated radiographs (at 6 weeks, and 3, 6, and 12 months) and magnetic resonance imaging (MR at 3 and 6 months) during the clinical trial.…”

Bone Marrow Multipotent Mesenchymal Stromal Cells as Autologous Therapy for Osteonecrosis: Effects of Age and Underlying Causes

“…In summary, the great potential of autologous MSCs alone or in combination with scaffolds and growth factors for tissue repair in ON is evident [ 6 , 48 ]. However, different ON-underlying factors could hamper the regenerative potential of autologous MSCs.…”

“…Autologous BM-MSCs can be delivered for regenerative therapies in their native form within BM aspirate concentrates or after culture expansion, aiming to achieve reparative effects with minor complications [ 33 , 200 , 201 , 202 , 203 ]. While native autologous MSCs used in BM aspirate concentrates were found to be effective and can be readily used [ 220 ], culture-expanded autologous MSCs have been proven safe and effective for treating ON in recent clinical evaluations [ 48 ]. Different tissue sources of MSCs may have better potential than BM-MSCs in conditions underlying ON, but further research is needed to confirm this idea.…”

Development of a human umbilical cord-derived mesenchymal stromal cell-based advanced therapy medicinal product to treat immune and/or inflammatory diseases

“…Bone marrow (BM) was proposed as the first source, autologous or allogeneic, to obtain MSCs [ 1 ]. Bone marrow-derived MSCs (BM-MSCs) have been described to participate in homeostasis and tissue repair and are thus investigated as tissue-engineered products in the field of regenerative medicine [ 2 ]. Later, umbilical cord-derived MSCs (UC-MSCs) have been described to display high immunomodulatory and anti-inflammatory properties [ 3 ], which has attracted attention for their use in the treatment of immune and/or inflammatory disorders.…”