Abstract
Purpose
Fracture healing encompasses a succession of dynamic multifactorial metabolic events, which ultimately re-establishes the integrity of the biomechanical properties of the bone. Up to 10% of the fractures occurring annually will need additional surgical procedures because of impaired healing. The aim of this article is to review the current literature regarding the use of bone marrow aspirate concentrate (BMAC) and its effectiveness in the management of bone defects.
Methods
We have included all published clinical literature investigating the development, techniques and applications of BMAC. Language, design and risk of bias did not deter the initial inclusion of any study. Our search was exclusively limited to studies involving human subjects. A PRISMA compliant search was carried out as published in 2009. This included the online databases: PubMed, EMBASE, clinical trial.gov and the Cochrane library from 1960 to the end of May 2015. MeSH terms used included: “Bone” AND “Marrow” AND “Aspirate” AND “Concentrate” AND “Bone Defects” AND “NONUNION”. Eligible studies were independently appraised by two authors using the Critical Appraisal Skills Program checklist. For the purpose of narrative review, relevant studies were included irrespective of methodology or level of evidence.
Results
Thirty-four of the 103 (48 PubMed and 55 EMBASE) results yielded by the preliminary search were included. Exclusions included three duplicate records, six letters, 17 non-orthopaedics related studies and four records irrelevant to our search topic. The CASP appraisal confirmed a satisfactory standard of 31 studies. They all had clearly defined objectives, were well designed and conducted appropriately to meet them. The published studies reported the use of BMAC in non-union and fracture healing (15 studies), bone defects (nine studies), spine fusion (two studies), distraction osteogensis (two studies) and complications related to the use of BMAC (seven studies).
Conclusions
Stem cells found in BMAC have the potential to self-renew, undertake clonal expansion and differentiate into different musculoskeletal tissues. The commercial processing of BMAC needs to be optimized in order to achieve a consistent end product, which will provide predicable and translatable results. The future potential of cell characterization in order to determine the optimum cell for repair/regeneration of bone also needs to be explored.
Level of Evidence: Systematic Review of minimum level IV studies.
Similar content being viewed by others
References
Einhorn TA (1995) Enhancement of fracture-healing. J Bone Joint Surg Am 77(6):940–956
Einhorn TA (1996) Enhancement of fracture healing. Instr Course Lect 45:401–416
Einhorn TA (1998) The cell and molecular biology of fracture healing. Clin Orthop Relat Res 355(Suppl):S7–21
Health Quality Ontario (2005) Osteogenic protein-1 for long bone nonunion: an evidence-based analysis. Ont Health Technol Assess Ser 5(6):1–57
Emara KM, Diab RA, Emara AK (2015) Recent biological trends in management of fracture non-union. World J Orthop 6(8):623–628. doi:10.5312/wjo.v6.i8.623
Hannouche D, Petite H, Sedel L (2001) Current trends in the enhancement of fracture healing. J Bone Joint Surg Br 83(2):157–164
Perren SM (2014) Fracture healing: fracture healing understood as the result of a fascinating cascade of physical and biological interactions. Part I. An attempt to integrate observations from 30 years AO research. Acta Chir Orthop Traumatol Cechoslov 81(6):355–364
Carofino BC, Lieberman JR (2008) Gene therapy applications for fracture-healing. J Bone Joint Surg Am 90(Suppl 1):99–110. doi:10.2106/JBJS.G.01546
Stevenson S (1998) Enhancement of fracture healing with autogenous and allogeneic bone grafts. Clin Orthop Relat Res 355(Suppl):S239–S246
Baksh D, Song L, Tuan RS (2004) Adult mesenchymal stem cells: characterization, differentiation, and application in cell and gene therapy. J Cell Mol Med 8(3):301–316
Gulotta LV, Kovacevic D, Ehteshami JR, Dagher E, Packer JD, Rodeo SA (2009) Application of bone marrow-derived mesenchymal stem cells in a rotator cuff repair model. Am J Sports Med 37(11):2126–2133. doi:10.1177/0363546509339582
Nejadnik H, Hui JH, Feng Choong EP, Tai BC, Lee EH (2010) Autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation: an observational cohort study. Am J Sports Med 38(6):1110–1116. doi:10.1177/0363546509359067
Imam MA, Mahmoud SSS, Holton J, Abouelmaati D, Elsherbini Y, Snow M (2017) A systematic review of the concept and clinical applications of bone marrow aspirate concentrate in orthopaedics. SICOT-J 3:17
Xie A, Nie L, Shen G, Cui Z, Xu P, Ge H, Tan Q (2014) The application of autologous plateletrich plasma gel in cartilage regeneration. Mol Med Rep 10(3):1642–1648. doi:10.3892/mmr.2014.2358
Majumdar MK, Thiede MA, Mosca JD, Moorman M, Gerson SL (1998) Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells. J Cell Physiol 176(1):57–66. doi:10.1002/(SICI)1097-4652(199807)176:1<57::AID-JCP7>3.0.CO;2-7
Hernigou P, Poignard A, Manicom O, Mathieu G, Rouard H (2005) The use of percutaneous autologous bone marrow transplantation in nonunion and avascular necrosis of bone. J Bone Joint Surg Br Vol 87(7):896–902. doi:10.1302/0301-620X.87B7.16289
Kassem MS (2013) Percutaneous autogenous bone marrow injection for delayed union or non union of fractures after internal fixation. Acta Orthop Belg 79(6):711–717
Nathan ST, Fisher BE, Roberts CS, Giannoudis PV (2011) The management of nonunion and delayed union of patella fractures: a systematic review of the literature. Int Orthop 35(6):791–795. doi:10.1007/s00264-010-1105-6
Lee DH, Ryu KJ, Kim JW, Kang KC, Choi YR (2014) Bone marrow aspirate concentrate and platelet-rich plasma enhanced bone healing in distraction osteogenesis of the tibia. Clin Orthop Relat Res 472(12):3789–3797. doi:10.1007/s11999-014-3548-3
Jager M, Jelinek EM, Wess KM, Scharfstadt A, Jacobson M, Kevy SV, Krauspe R (2009) Bone marrow concentrate: a novel strategy for bone defect treatment. Curr Stem Cell Res Ther 4(1):34–43
Muschler GF, Nitto H, Matsukura Y, Boehm C, Valdevit A, Kambic H, Davros W, Powell K, Easley K (2003) Spine fusion using cell matrix composites enriched in bone marrow-derived cells. Clin Orthop Relat Res 407:102–118
McCarrel T, Fortier L (2009) Temporal growth factor release from platelet-rich plasma, trehalose lyophilized platelets, and bone marrow aspirate and their effect on tendon and ligament gene expression. J Orthop Res 27(8):1033–1042. doi:10.1002/jor.20853
Wilkins RM, Kelly CM (2003) The effect of allomatrix injectable putty on the outcome of long bone applications. Orthopedics 26(5 Suppl):s567–s570
Fortier LA, Potter HG, Rickey EJ, Schnabel LV, Foo LF, Chong LR, Stokol T, Cheetham J, Nixon AJ (2010) Concentrated bone marrow aspirate improves full-thickness cartilage repair compared with microfracture in the equine model. J Bone Joint Surg Am 92(10):1927–1937. doi:10.2106/JBJS.I.01284
Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62(10):1006–1012. doi:10.1016/j.jclinepi.2009.06.005
Hyde M, Higgs P, Wiggins RD, Blane D (2015) A decade of research using the CASP scale: key findings and future directions. Aging Ment Health 19(7):571–575. doi:10.1080/13607863.2015.1018868
Goel A, Sangwan SS, Siwach RC, Ali AM (2005) Percutaneous bone marrow grafting for the treatment of tibial non-union. Injury 36(1):203–206. doi:10.1016/j.injury.2004.01.009
Siwach RC, Sangwan SS, Singh R, Goel A (2001) Role of percutaneous bone marrow grafting in delayed unions, non-unions and poor regenerates. Indian J Med Sci 55(6):326–336
Matsuda Y, Sakayama K, Okumura H, Kawatani Y, Mashima N, Shibata T (1998) Percutaneous autologous bone marrow transplantation for nonunion of the femur. Nihon Geka Hokan 67(1):10–17
Garg NK, Gaur S, Sharma S (1993) Percutaneous autogenous bone marrow grafting in 20 cases of ununited fracture. Acta Orthop Scand 64(6):671–672
Hernigou P, Mathieu G, Poignard A, Manicom O, Beaujean F, Rouard H (2006) Percutaneous autologous bone-marrow grafting for nonunions. Surgical technique. J Bone Joint Surg Am 88(Suppl 1 Pt 2):322–327. doi:10.2106/JBJS.F.00203
Desai P, Hasan SM, Zambrana L, Hegde V, Saleh A, Cohn MR, Lane JM (2015) Bone mesenchymal stem cells with growth factors successfully treat nonunions and delayed unions. HSS J 11(2):104–111. doi:10.1007/s11420-015-9432-1
Hernigou P, Guissou I, Homma Y, Poignard A, Chevallier N, Rouard H, Flouzat Lachaniette CH (2015) Percutaneous injection of bone marrow mesenchymal stem cells for ankle non-unions decreases complications in patients with diabetes. Int Orthop. doi:10.1007/s00264-015-2738-2
Akcay S, Kazimoglu C (2014) Bone marrow aspirate concentrate and platelet-rich plasma enhanced bone healing in distraction osteogenesis of the tibia. Clin Orthop Relat Res 472(7):2301–2302. doi:10.1007/s11999-014-3637-3
Hernigou P, Beaujean F (2002) Treatment of osteonecrosis with autologous bone marrow grafting. Clin Orthop Relat Res 405:14–23
Jager M, Herten M, Fochtmann U, Fischer J, Hernigou P, Zilkens C, Hendrich C, Krauspe R (2011) Bridging the gap: bone marrow aspiration concentrate reduces autologous bone grafting in osseous defects. J Orthop Res 29(2):173–180. doi:10.1002/jor.21230
Hernigou P, Poignard A, Beaujean F, Rouard H (2005) Percutaneous autologous bone-marrow grafting for nonunions. Influence of the number and concentration of progenitor cells. J Bone Joint Surg Am 87(7):1430–1437. doi:10.2106/JBJS.D.02215
Petri M, Namazian A, Wilke F, Ettinger M, Stubig T, Brand S, Bengel F, Krettek C, Berding G, Jagodzinski M (2013) Repair of segmental long-bone defects by stem cell concentrate augmented scaffolds: a clinical and positron emission tomography--computed tomography analysis. Int Orthop 37(11):2231–2237. doi:10.1007/s00264-013-2087-y
Sauerbier S, Rickert D, Gutwald R, Nagursky H, Oshima T, Xavier SP, Christmann J, Kurz P, Menne D, Vissink A, Raghoebar G, Schmelzeisen R, Wagner W, Koch FP (2011) Bone marrow concentrate and bovine bone mineral for sinus floor augmentation: a controlled, randomized, single-blinded clinical and histological trial--per-protocol analysis. Tissue Eng A 17(17–18):2187–2197. doi:10.1089/ten.TEA.2010.0516
Rickert D, Sauerbier S, Nagursky H, Menne D, Vissink A, Raghoebar GM (2011) Maxillary sinus floor elevation with bovine bone mineral combined with either autogenous bone or autogenous stem cells: a prospective randomized clinical trial. Clin Oral Implants Res 22(3):251–258. doi:10.1111/j.1600-0501.2010.01981.x
Kitoh H, Kitakoji T, Tsuchiya H, Mitsuyama H, Nakamura H, Katoh M, Ishiguro N (2004) Transplantation of marrow-derived mesenchymal stem cells and platelet-rich plasma during distraction osteogenesis--a preliminary result of three cases. Bone 35(4):892–898. doi:10.1016/j.bone.2004.06.013
Hendrich C, Franz E, Waertel G, Krebs R, Jager M (2009) Safety of autologous bone marrow aspiration concentrate transplantation: initial experiences in 101 patients. Orthop Rev 1(2):e32. doi:10.4081/or.2009.e32
Donaldson S, Chundamala J, Yandow S, Wright JG (2010) Treatment for unicameral bone cysts in long bones: an evidence based review. Orthop Rev 2(1):e13. doi:10.4081/or.2010.e13
Di Bella C, Dozza B, Frisoni T, Cevolani L, Donati D (2010) Injection of demineralized bone matrix with bone marrow concentrate improves healing in unicameral bone cyst. Clin Orthop Relat Res 468(11):3047–3055. doi:10.1007/s11999-010-1430-5
Gan Y, Dai K, Zhang P, Tang T, Zhu Z, Lu J (2008) The clinical use of enriched bone marrow stem cells combined with porous beta-tricalcium phosphate in posterior spinal fusion. Biomaterials 29(29):3973–3982. doi:10.1016/j.biomaterials.2008.06.026
Bain BJ (2005) Bone marrow biopsy morbidity: review of 2003. J Clin Pathol 58(4):406–408. doi:10.1136/jcp.2004.022178
Burkle CM, Harrison BA, Koenig LF, Decker PA, Warner DO, Gastineau DA (2004) Morbidity and mortality of deep sedation in outpatient bone marrow biopsy. Am J Hematol 77(3):250–256. doi:10.1002/ajh.20185
Bain BJ (2004) Bone marrow biopsy morbidity and mortality: 2002 data. Clin Lab Haematol 26(5):315–318. doi:10.1111/j.1365-2257.2004.00630.x
Bain BJ (2003) Bone marrow biopsy morbidity and mortality. Br J Haematol 121(6):949–951
Hernigou J, Picard L, Alves A, Silvera J, Homma Y, Hernigou P (2014) Understanding bone safety zones during bone marrow aspiration from the iliac crest: the sector rule. Int Orthop 38(11):2377–2384. doi:10.1007/s00264-014-2343-9
Husebye EE, Lyberg T, Roise O (2006) Bone marrow fat in the circulation: clinical entities and pathophysiological mechanisms. Injury 37(Suppl 4):S8–18. doi:10.1016/j.injury.2006.08.036
Orlowski JP, Julius CJ, Petras RE, Porembka DT, Gallagher JM (1989) The safety of intraosseous infusions: risks of fat and bone marrow emboli to the lungs. Ann Emerg Med 18(10):1062–1067
Acknowledgements
We acknowledge the support of library staff of Royal Orthopaedic NHS Foundation Trust, UK.
Funding
Self-funded.
Author information
Authors and Affiliations
Contributions
All authors conceptualized the study and participated in study screening, selection, data extraction and manuscript preparation. All authors provided intellectual content and approved the manuscript for publication.
Corresponding author
Ethics declarations
Conflict of interest
NOne.
Additional information
The paper has not been submitted to any other journal.
Rights and permissions
About this article
Cite this article
Imam, M.A., Holton, J., Ernstbrunner, L. et al. A systematic review of the clinical applications and complications of bone marrow aspirate concentrate in management of bone defects and nonunions. International Orthopaedics (SICOT) 41, 2213–2220 (2017). https://doi.org/10.1007/s00264-017-3597-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00264-017-3597-9