title: Development of a simple procedure for the treatment of femoral head osteonecrosis with intra-osseous injection of bone marrow mesenchymal stromal cells: study of their biodistribution in the early time points after injection.
abstract: BACKGROUND
  Osteonecrosis of the femoral head (ONFH) is a degenerative disease progressing to a femoral head (FH) collapse. Injection of osteoprogenitor cells like bone marrow mesenchymal stromal cells (BMSCs) into the FH appears to be a good therapeutic treatment. However, safety and efficacy of BMSCs to treat bone defect are the main preclinical data required for clinical application. Efficacy and the lack of risk of cell transformation after amplification of BMSCs have been extensively described. The main objectives of this study were to develop a simple and usable procedure for clinicians and control its feasibility by evaluating the biodistribution of BMSCs after injection into the FH in a large animal model. The impact of this approach was evaluated on one natural pig ONFH.
  
  
  METHODS
  BMSCs were directly injected in the pig FH, and then the biodistribution of grafted cells was detected by quantitative real-time polymerase chain reaction, cytometry, or a combination of classic histology analysis and in situ hybridization (ISH). BMSC efficacy on bone regeneration was evaluated by magnetic resonance imaging (MRI) and histology.
  
  
  RESULTS
  After 30-minute and 24-hour follow-up, grafted cells were detected at the injection site and no BMSCs were detected in filter organs or body fluids. The combination of classic histology analysis and ISH showed a good homogeneity of cell distribution in FH. Local delivery of BMSCs onto a bone scaffold associated with bone formation in vivo confirmed the preferential tropism of BMSCs to the bone tissue as well as their efficacy to form bone. Treatment of a natural pig ONFH by autologous BMSCs indicated a beginning of bone healing as early as 2 weeks with a complete healing after 9 weeks. At this stage, MRI and histological analysis were similar to those of a normal FH.
  
  
  CONCLUSIONS
  Intra-osseous injection of BMSCs in FH seems to be a good strategy for ONFH treatment as the safety concerning the biodistribution of BMSCs is ensured. Moreover, the efficacy of BMSCs in natural ONFH seems to indicate that this is a promising approach. Altogether, these results constitute the preclinical data necessary for the setup of a clinical application with expanded BMSCs in the context of advanced therapy medicinal products.
authors.affiliation: Université Paris-Est, Faculté de médecine, Laboratoire de "Bioingénierie cellulaire, tissulaire et sanguine", EA3952, 5 rue Gustave Eiffel, 94000, Créteil, France. angelique.lebouvier@gmail.com.|Etablissement Français du Sang d'Ile-de-France, Unité d'Ingénierie et de Thérapie Cellulaire, 5 rue Gustave Eiffel, 94017, Créteil cedex, France. angelique.lebouvier@gmail.com.|Inserm UMR955, IMRB, 51 Avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France. angelique.lebouvier@gmail.com.
authors.forename: Angélique
authors.initials: A
authors.lastname: Lebouvier
authors.affiliation: Université Paris-Est, Faculté de médecine, Laboratoire de "Bioingénierie cellulaire, tissulaire et sanguine", EA3952, 5 rue Gustave Eiffel, 94000, Créteil, France. alexandre.poignard@hmn.aphp.fr.|Inserm UMR955, IMRB, 51 Avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France. alexandre.poignard@hmn.aphp.fr.|Service de chirurgie orthopédique et traumatologie, AP-HP Hôpital Henri-Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France. alexandre.poignard@hmn.aphp.fr.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Poignard
authors.affiliation: Service de radiologie Albert Chenevier, AP-HP Hôpital Henri-Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France. mcavet@gmail.com.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Cavet
authors.affiliation: Inserm U957, Laboratory for Pathophysiology of Bone Resorption, Faculty of Medicine, University of Nantes, 1 rue Gaston Veil, 44035, Nantes cedex 1, France. jerome.amiaud@univ-nantes.fr.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Amiaud
authors.affiliation: Université Paris-Est, Faculté de médecine, Laboratoire de "Bioingénierie cellulaire, tissulaire et sanguine", EA3952, 5 rue Gustave Eiffel, 94000, Créteil, France. leotot.julie@orange.fr.|Etablissement Français du Sang d'Ile-de-France, Unité d'Ingénierie et de Thérapie Cellulaire, 5 rue Gustave Eiffel, 94017, Créteil cedex, France. leotot.julie@orange.fr.|Inserm UMR955, IMRB, 51 Avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France. leotot.julie@orange.fr.
authors.forename: Julie
authors.initials: J
authors.lastname: Leotot
authors.affiliation: Université Paris-Est, Faculté de médecine, Laboratoire de "Bioingénierie cellulaire, tissulaire et sanguine", EA3952, 5 rue Gustave Eiffel, 94000, Créteil, France. philippe.hernigou@hmn.aphp.fr.|Inserm UMR955, IMRB, 51 Avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France. philippe.hernigou@hmn.aphp.fr.|Service de chirurgie orthopédique et traumatologie, AP-HP Hôpital Henri-Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France. philippe.hernigou@hmn.aphp.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Hernigou
authors.affiliation: Service de radiologie Albert Chenevier, AP-HP Hôpital Henri-Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France. alain.rahmouni@hmn.aphp.fr.
authors.forename: Alain
authors.initials: A
authors.lastname: Rahmouni
authors.affiliation: Etablissement Français du Sang d'Ile-de-France, Unité d'Ingénierie et de Thérapie Cellulaire, 5 rue Gustave Eiffel, 94017, Créteil cedex, France. philippe.bierling@efs.sante.fr.|Inserm UMR955, IMRB, 51 Avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France. philippe.bierling@efs.sante.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bierling
authors.affiliation: Inserm U957, Laboratory for Pathophysiology of Bone Resorption, Faculty of Medicine, University of Nantes, 1 rue Gaston Veil, 44035, Nantes cedex 1, France. pierre.layrolle@inserm.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Layrolle
authors.affiliation: Université Paris-Est, Faculté de médecine, Laboratoire de "Bioingénierie cellulaire, tissulaire et sanguine", EA3952, 5 rue Gustave Eiffel, 94000, Créteil, France. helene.rouard@efs.sante.fr.|Etablissement Français du Sang d'Ile-de-France, Unité d'Ingénierie et de Thérapie Cellulaire, 5 rue Gustave Eiffel, 94017, Créteil cedex, France. helene.rouard@efs.sante.fr.|Inserm UMR955, IMRB, 51 Avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France. helene.rouard@efs.sante.fr.|AP-HP Hôpital Henri-Mondor - A. Chenevier, Service hospitalier, 51 Avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France. helene.rouard@efs.sante.fr.
authors.forename: Hélène
authors.initials: H
authors.lastname: Rouard
authors.affiliation: Université Paris-Est, Faculté de médecine, Laboratoire de "Bioingénierie cellulaire, tissulaire et sanguine", EA3952, 5 rue Gustave Eiffel, 94000, Créteil, France. nathalie.chevallier@efs.sante.fr.|Etablissement Français du Sang d'Ile-de-France, Unité d'Ingénierie et de Thérapie Cellulaire, 5 rue Gustave Eiffel, 94017, Créteil cedex, France. nathalie.chevallier@efs.sante.fr.|Inserm UMR955, IMRB, 51 Avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France. nathalie.chevallier@efs.sante.fr.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chevallier
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D001842:Bone and Bones / Q000473:pathology; D005260:Female; D005270:Femur Head / Q000000981:diagnostic imaging / Q000473:pathology; D005271:Femur Head Necrosis / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D006801:Humans; D017148:Infusions, Intraosseous; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D010012:Osteogenesis; D011859:Radiography; D060888:Real-Time Polymerase Chain Reaction; D043262:Ribonuclease P / Q000235:genetics; D013552:Swine; D014018:Tissue Distribution; D014182:Transplantation, Autologous; D014183:Transplantation, Heterologous
chemical_list: D043262:Ribonuclease P