title: Non-Hematopoietic Essential Functions of Bone Marrow Cells: A Review of Scientific and Clinical Literature and Rationale for Treating Bone Defects.
abstract: Hematopoiesis as the only essential function of bone marrow cells has been challenged for several decades through basic science (in vitro and in vivo) and clinical data. Such work has shed light on two other essential functions of bone marrow cells: osteopoiesis and angio-genesis/vasculogenesis. Clinical utility of autologous concentrated bone marrow aspirate (CBMA) has demonstrated both safety and efficacy in treating bone defects. Moreover, CBMA has been shown to be comparable to the gold standard of iliac crest bone graft (ICBG), or autograft, with regard to being osteogenic and osteoinductive. ICBG is not considered an advanced therapy medicinal product (ATMP), but CBMA may become regulated as an ATMP. The European Medicines Agency Committee for Advanced Therapies (EMA:CAT) has issued a reflection paper (20 June 2014) in which reversal of the 2013 ruling that CBMA is a non-ATMP has been proposed. We review bone marrow cell involvement in osteopoiesis and angiogenesis/vasculogenesis to examine EMA:CAT 2013 decision to use CBMA for treatment of osteonecrosis (e.g, of the femoral head) should be considered a non-ATMP. This paper is intended to provide discussion on the 20 June 2014 reflection paper by reviewing two non-hematopoietic essential functions of bone marrow cells. Additionally, we provide clinical and scientific rationale for treating osteonecrosis with CBMA.
authors.affiliation: Harrell BioScience Consulting LLC , Quincy, MA, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Harrell
authors.affiliation: Department of Cardiovascular Disease, Fondazione de Ricerca e Cura Giovanni e Paolo II , Campbasso, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Caradonna
authors.affiliation: Blood Component and Regenerative Medicine Laboratory, Alessandria Hospital , Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mazzucco
authors.affiliation: Granzer Regulatory Consulting and Services , München, Germany.
authors.forename: Rosmarie
authors.initials: R
authors.lastname: Gudenus
authors.affiliation: ASKLEPIOS Westklinikum Hamburg , Germany.
authors.forename: Berthold
authors.initials: B
authors.lastname: Amann
authors.affiliation: Interventional Neuroradiology and Angiology, University of Ostrava , Czech Republic.
authors.forename: Vaclav
authors.initials: V
authors.lastname: Prochazka
authors.affiliation: Trauma and Orthopedic Surgery School of Medicine, University of Leeds , UK.
authors.forename: Peter V
authors.initials: PV
authors.lastname: Giannoudis
authors.affiliation: Orthopaedishe Krankenhaus Schloss Werneck, Werneck Bayern , Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hendrich
authors.affiliation: Universitätklinikum Essen , Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Jäger
authors.affiliation: Klinik Orthopaedische, University of Düsseldorf , Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Krauspe
authors.affiliation: Hôspital Henri Mondor , Creteil, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Hernigou
keywords: Concentrated bone marrow aspirate; angiogenesis; hematopoiesis; osteonecrosis; osteopoiesis