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Editorial Commentary: Bone Marrow Aspirate Concentrate: Time to Harvest Locally?

      Abstract

      Cell therapies hold great promise as primary and adjuvant treatments for a range of musculoskeletal conditions. Bone marrow harvested from the iliac crest represents the gold-standard source of progenitor cells with a recognized ability to release trophic factors, modulate local immune environments, and differentiate into multiple musculoskeletal cell types in vitro. Identifying accessible locations that limit donor-site morbidity while increasing efficiency during aspiration of bone marrow is essential. There is increasing evidence to suggest that the number of progenitor cells present in bone marrow aspirated from multiple sites, including the proximal humerus and ilium, is at least equivalent to that from the iliac crest. Because many of these sources lie within the surgical field, the requirement for iliac crest harvest and the risks associated with secondary harvest sites can be mitigated. Although there is a clear need for further studies evaluating the biological attributes and clinical benefit of bone marrow aspirate concentrate in a range of clinical settings, the use of local harvesting sites is likely to reduce morbidity and improve the experience for patients.
      Bone marrow is recognized to contain cells and growth factors that contribute to healing and have pro-regenerative properties in vitro.
      • LaPrade R.F.
      • Dragoo J.L.
      • Koh J.L.
      • et al.
      AAOS research symposium updates and consensus: Biologic treatment of orthopaedic injuries.
      ,
      • LaPrade R.F.
      • Geeslin A.G.
      • Murray I.R.
      • et al.
      Biologic Treatments for Sports Injuries II Think Tank—Current concepts, future research, and barriers to advancement, part 1: Biologics overview, ligament injury, tendinopathy.
      Cells within bone marrow with the capacity to multiply (“self-renew”), generating colonies of cells that can differentiate into multiple musculoskeletal lineages, modify the immune environment, and release trophic factors, have attracted particular attention. Although the nomenclature used to describe similar populations has evolved over the past 20 years,
      • Murray I.R.
      • Chahla J.
      • Safran M.R.
      • et al.
      International expert consensus on a cell therapy communication tool: DOSES.
      terms such as “connective tissue progenitor” and “medicinal signaling cell” are currently thought to best reflect the nature and characteristics of these cells.
      • Caplan A.I.
      Mesenchymal stem cells: Time to change the name!.
      To maximize the number of progenitor cells delivered, strategies to concentrate bone marrow aspirate (producing bone marrow aspirate concentrate [BMAC]) while separating out layers of fat and blood have increased in popularity.
      • Chahla J.
      • Dean C.S.
      • Moatshe G.
      • et al.
      Concentrated bone marrow aspirate for the treatment of chondral injuries and osteoarthritis of the knee: A systematic review of outcomes.
      Bone marrow represents a particularly attractive substrate for regenerative medicine, given its relative accessibility, abundant supply, and the potential for point-of-care use. However, its use is currently limited by donor-site morbidity, preparation heterogeneity, and concerns relating to lower regeneration efficiency compared with purer populations because coexisting cell types may have inhibitory effects on progenitor cells.
      • Murray I.R.
      • Corselli M.
      • Petrigliano F.A.
      • et al.
      Recent insights into the identity of mesenchymal stem cells: Implications for orthopaedic applications.
      We were very pleased to review the excellent article entitled “Proximal Humerus and Ilium Are Reliable Sources of Bone Marrow Aspirates for Biologic Augmentation During Arthroscopic Surgery” by Otto, Muench, Kia, Baldino, Mehl, Dyrna, Voss, McCarthy, Nazal, Martin, and Mazzocca,
      • Otto A.
      • Muench L.N.
      • Kia C.
      • et al.
      Proximal humerus and ilium are reliable sources of bone marrow aspirates for biologic augmentation during arthroscopic surgery.
      which was an international collaborative study seeking to address some of these key challenges. Otto et al. evaluated the potential biological harvest of bone marrow aspirate from the proximal humerus during a rotator cuff repair and the acetabular portion of the ilium during acetabular labral repair, representing local sources of bone marrow aspirate that would negate the need for harvest from a second site and the associated morbidity. Furthermore, this collaborative study sought to better characterize BMAC isolated from these sites, performing a comprehensive analysis of samples including an evaluation of the number of colony-forming units (CFUs). Over a 4-year period, the authors were able to successfully obtain CFUs from both the proximal humerus and the acetabulum, with a significant increase in the number of units grown from the proximal humerus in this cohort. Of significant note, they obtained the bone marrow harvest from proximal humeral sites that would normally be used for anchor repairs of the rotator cuff.
      The iliac crest has traditionally been considered the benchmark source for bone marrow harvest.
      • McLain R.F.
      • Fleming J.E.
      • Boehm C.A.
      • et al.
      Aspiration of osteoprogenitor cells for augmenting spinal fusion: Comparison of progenitor cell concentrations from the vertebral body and iliac crest.
      The study by Otto et al.
      • Otto A.
      • Muench L.N.
      • Kia C.
      • et al.
      Proximal humerus and ilium are reliable sources of bone marrow aspirates for biologic augmentation during arthroscopic surgery.
      adds weight to an increasing body of literature showing that multiple sites of bone marrow aspirate yield numbers of CFUs at least as plentiful as aspirations from the iliac crest.
      • McLain R.F.
      • Fleming J.E.
      • Boehm C.A.
      • et al.
      Aspiration of osteoprogenitor cells for augmenting spinal fusion: Comparison of progenitor cell concentrations from the vertebral body and iliac crest.
      • Nazal M.R.
      • McCarthy M.B.R.
      • Mazzocca A.D.
      • et al.
      Connective tissue progenitor analysis of bone marrow aspirate concentrate harvested from the body of the ilium during arthroscopic acetabular labral repair.
      • Beitzel K.
      • McCarthy M.B.
      • Cote M.P.
      • et al.
      Comparison of mesenchymal stem cells (osteoprogenitors) harvested from proximal humerus and distal femur during arthroscopic surgery.
      • Hernigou P.
      • Poignard A.
      • Beaujean F.
      • et al.
      Percutaneous autologous bone-marrow grafting for nonunions. Influence of the number and concentration of progenitor cells.
      In addition, the yield of CFUs does not seem to be influenced by age, body mass index, or medical comorbidities, indicating that it represents a “universal” source of progenitors for regenerative medicine in all patients. A site of bone marrow aspiration that is accessible within the surgical field allows for single-stage, intraoperative harvest and application while minimizing potential morbidity and resource use involved in harvest from 2 separate locations. Primum non nocere—Hippocrates wrote of first doing no harm.

      Hippocrate/Kuhn, Karl Gottlob, ed. Magni Hippocratis Opera Omnia (tomus III, 395) Leipzig: Car Cnoblochii, 1827. http://www.biusante.parisdescartes.fr/histmed/medica/cote?hippokuhnx03. Accessed June 20, 2020.

      The current study and others support the case that we may no longer have to expose our patients to the additional morbidity of a second surgical site for bone marrow aspiration.
      Although the mesenchymal progenitors within bone marrow aspirate garner the most attention, it should also be considered that BMAC represents a heterogeneous soup containing numerous growth factors and non-mesenchymal cells, including endothelial cells, as well as hematopoietic and inflammatory cells. A number of studies have raised the concern that the present non-progenitor fraction of cells may negatively influence the regenerative attributes of bone marrow aspirate. As such, future work should seek not just to characterize and quantify those cells proliferating in culture conditions but also to analyze all aspects of biological preparations as they appear at the point of delivery. This analysis should include characterization of all cell types and growth factors present and their interactions.
      • Murray I.R.
      • Corselli M.
      • Petrigliano F.A.
      • et al.
      Recent insights into the identity of mesenchymal stem cells: Implications for orthopaedic applications.
      Paramount to the clinical translation of basic research into adult stem cell therapies is a comprehensive characterization and understanding of the regenerative properties of delivered preparations. Although autologous, minimally manipulated preparations avoid the potential risks associated with processing or culturing of cells, the regenerative characteristics of these heterogeneous preparations have remained poorly understood.
      • Murray I.R.
      • Corselli M.
      • Petrigliano F.A.
      • et al.
      Recent insights into the identity of mesenchymal stem cells: Implications for orthopaedic applications.
      Through this study and previously published work, the authors have contributed a comprehensive evaluation of CFUs, flow cytometric analysis, and differentiation capacity assays of bone marrow from multiple sites.
      • Otto A.
      • Muench L.N.
      • Kia C.
      • et al.
      Proximal humerus and ilium are reliable sources of bone marrow aspirates for biologic augmentation during arthroscopic surgery.
      ,
      • Nazal M.R.
      • McCarthy M.B.R.
      • Mazzocca A.D.
      • et al.
      Connective tissue progenitor analysis of bone marrow aspirate concentrate harvested from the body of the ilium during arthroscopic acetabular labral repair.
      Critically, this group has taken great care to include important details of the methods and processes that may critically influence outcomes, allowing other investigators to interpret and replicate their studies. This is significant because an inadequate description of processing protocols has so far limited the interpretation and definite comparisons between studies.
      • Chahla J.
      • Cinque M.E.
      • Piuzzi N.S.
      • et al.
      A call for standardization in platelet-rich plasma preparation protocols and composition reporting: A systematic review of the clinical orthopaedic literature.
      Similarly, the nomenclature used throughout these authors’ work is defined and standardized. We believe strongly that transparency of protocols and increased standards in methods used to process, evaluate, and describe biological therapies are necessary to drive this exciting field forward.
      • Murray I.R.
      • Chahla J.
      • Safran M.R.
      • et al.
      International expert consensus on a cell therapy communication tool: DOSES.
      ,
      • Murray I.R.
      • Geeslin A.G.
      • Goudie E.B.
      • et al.
      Minimum information for studies evaluating biologics in orthopaedics (MIBO): Platelet-rich plasma and mesenchymal stem cells.
      Although studies have reported improved outcomes after BMAC therapy in a range of clinical settings,
      • Chahla J.
      • Dean C.S.
      • Moatshe G.
      • et al.
      Concentrated bone marrow aspirate for the treatment of chondral injuries and osteoarthritis of the knee: A systematic review of outcomes.
      ,
      • Cavinatto L.
      • Hinckel B.B.
      • Tomlinson R.E.
      • et al.
      The role of bone marrow aspirate concentrate for the treatment of focal chondral lesions of the knee: A systematic review and critical analysis of animal and clinical studies.
      there is currently insufficient evidence to support its widespread application.
      • LaPrade R.F.
      • Dragoo J.L.
      • Koh J.L.
      • et al.
      AAOS research symposium updates and consensus: Biologic treatment of orthopaedic injuries.
      ,
      • LaPrade R.F.
      • Geeslin A.G.
      • Murray I.R.
      • et al.
      Biologic Treatments for Sports Injuries II Think Tank—Current concepts, future research, and barriers to advancement, part 1: Biologics overview, ligament injury, tendinopathy.
      In addition to well-designed studies evaluating clinical effectiveness, future research should continue to evaluate the attributes and regenerative characteristics of BMAC. Particularly when ambiguity on clinical effectiveness remains, we always consider the risk-benefit balance in making treatment decisions with patients. Although negating the need for a separate harvest site may not completely tip this balance, the harvesting of bone marrow from local sites based on evidence from studies such as that of Otto et al.
      • Otto A.
      • Muench L.N.
      • Kia C.
      • et al.
      Proximal humerus and ilium are reliable sources of bone marrow aspirates for biologic augmentation during arthroscopic surgery.
      may reduce morbidity and costs associated with secondary harvest sites and improve the experience for patients.

      Supplementary Data

      References

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      1. Hippocrate/Kuhn, Karl Gottlob, ed. Magni Hippocratis Opera Omnia (tomus III, 395) Leipzig: Car Cnoblochii, 1827. http://www.biusante.parisdescartes.fr/histmed/medica/cote?hippokuhnx03. Accessed June 20, 2020.

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