Autologous mesenchymal stem cell implantation, hydroxyapatite, bone morphogenetic protein-2, and internal fixation for treating critical-sized defects: a translational study

Ismail Hadisoebroto Dilogo, Phedy Phedy, Erica Kholinne, Yoshi Pratama Djaja, Jessica Fiolin, Yuyus Kusnadi, Nyimas Diana Yulisa, Ismail Hadisoebroto Dilogo, Phedy Phedy, Erica Kholinne, Yoshi Pratama Djaja, Jessica Fiolin, Yuyus Kusnadi, Nyimas Diana Yulisa

Abstract

Introduction: Critical-sized defect (CSD) is one of the most challenging cases for orthopaedic surgeons. We aim to explore the therapeutic potential of the combination of bone marrow-derived mesenchymal stem cells (BM-MSCs), hydroxyapatite (HA) granules, bone morphogenetic protein-2 (BMP-2), and internal fixation for treating CSDs.

Methods: This was a translational study performed during the period of January 2012 to 2016. Subjects were patients diagnosed with CSDs who had previously failed surgical attempts. They were treated with the combination of autologous BM-MSCs, HA granules, BMP-2, and mechanical stabilization. Post-operative pain level, functional outcome, defect volume, and radiological healing were evaluated after a minimum follow-up of 12 months.

Results: A total of six subjects were recruited in this study. The pain was significantly reduced in all cases; with the decrease of mean preoperative visual analog scale (VAS) from 4 ± 2.2 to 0 after six month follow-up. Clinical functional outcome percentage increased significantly from 25 ± 13.7 to 70.79 ± 19.5. Radiological healing assessment using Tiedemann score also showed an increase from 0.16 ± 0.4 to 8 ± 3 at one year follow-up. No immunologic nor neoplastic side effects were found.

Conclusions: The combination of autologous BM-MSCs, HA granules, and BMP-2 is safe and remains to be a good option for the definitive treatment for CSD with previous failed surgical attempts. Further studies with a larger sample size are required to be done.

Trial registration: ClinicalTrials.gov NCT01725698.

Keywords: Autologous; BMP-2; Critical-sized bone defect; Mesenchymal stem cell; Union.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Volume defect measurement by means of radiography
Fig. 2
Fig. 2
An 18-year-old male (case 1) with 5-cm bone defect of the humerus. a Pre-operative radiography. b Post-operative radiography. c Two-month post-operative radiography. d Six-month post-operative radiography. e Twelve-month post-operative radiography
Fig. 3
Fig. 3
A 34-year-old male (case 2) diagnosed with infected open fracture of the right distal femur with 7-cm bone defect after Masquelet procedure. a Pre-operative radiography. b Post-operative radiography, c Twelve-month radiography. d Twenty-one-month radiography
Fig. 4
Fig. 4
A 24-year-old female (case 3) with 12 cm BD of the tibia. a Initial radiography. b Pre-operative radiography. c Post-operative radiography. d Six-month radiography. e Fifteen-month post-operative radiography
Fig. 5
Fig. 5
A 28-year-old male (case 4) with 7-year history of 8-cm bone defect of the right tibia. a Initial x-ray and clinical picture after external fixation removal. b Pre-operative radiography. c Post-operative, d Five-month radiography. e Twelve-month radiography
Fig. 6
Fig. 6
A 33-year-old male (case 5) with 6-cm bone defect of the tibia. a Initial radiography. b Pre-operative radiography. c Post-operative radiography. d Six-month post-operative radiography. e Twelve-month post-operative radiography
Fig. 7
Fig. 7
A 40-year-old female with 5 years of 6-cm bone defect of the femur. a Pre-operative radiography. b Post-operative radiography. c Six-month post-operative radiography. d Twelve-month post-operative radiography. e Four-year post-operative radiography

References

    1. Schmidmaier G, Capanna R, Wildemann B, et al. Bone morphogenetic proteins in critical-size bone defects: what are the options? Injury. 2009;40:S39–S43. doi: 10.1016/S0020-1383(09)70010-5.
    1. Li Y, Chen SK, Li L, et al. Bone defect animal models for testing efficacy of bone substitute biomaterials. J Orthop Transl. 2015;3:95–104.
    1. Mauffrey C, Barlow BT, Smith W. Management of segmental bone defects. J Am Acad Orthop Surg. 2015;23:143–153.
    1. Nauth A, McKee MD, Einhorn TA, et al. Managing bone defects. J Orthop Trauma. 2011;25:462–466. doi: 10.1097/BOT.0b013e318224caf0.
    1. Reichert JC, Saifzadeh S, Wullschleger ME, et al. The challenge of establishing preclinical models for segmental bone defect research. Biomaterials. 2009;30:2149–2163. doi: 10.1016/j.biomaterials.2008.12.050.
    1. Perka C, Schultz O, Spitzer RS, et al. Segmental bone repair by tissue-engineered periosteal cell transplants with bioresorbable fleece and fibrin scaffolds in rabbits. Biomaterials. 2000;21:1145–1153. doi: 10.1016/S0142-9612(99)00280-X.
    1. Komaki H, Tanaka T, Chazono M, Kikuchi T. Repair of segmental bone defects in rabbit tibiae using a complex of beta-tricalcium phosphate, type I collagen, and fibroblast growth factor-2. Biomaterials. 2006;27:5118–5126. doi: 10.1016/j.biomaterials.2006.05.031.
    1. Liu G, Zhao L, Zhang W, et al. Repair of goat tibial defects with bone marrow stromal cells and beta-tricalcium phosphate. J Mater Sci Mater Med. 2008;19:2367–2376. doi: 10.1007/s10856-007-3348-3.
    1. Gao TJ, Lindholm TS, Kommonen B, et al. Enhanced healing of segmental tibial defects in sheep by a composite bone substitute composed of tricalcium phosphate cylinder, bone morphogenetic protein, and type IV collagen. J Biomed Mater Res. 1996;32:505–512. doi: 10.1002/(SICI)1097-4636(199612)32:4<505::AID-JBM2>;2-V.
    1. Bucholz RW, Carlton A, Holmes R (1989) Interporous hydroxyapatite as a bone graft substitute in tibial plateau fractures. Clin Orthop Relat Res 240:53–62
    1. Blokhuis TJ, Wippermann BW, Den Boer FC, et al. Resorbable calcium phosphate particles as a carrier material for bone marrow in an ovine segmental defect. J Biomed Mater Res. 2000;51:369–375. doi: 10.1002/1097-4636(20000905)51:3<369::AID-JBM10>;2-J.
    1. Oest ME, Dupont KM, Kong HJ, et al. Quantitative assessment of scaffold and growth factor-mediated repair of critically sized bone defects. J Orthop Res. 2007;25:941–950. doi: 10.1002/jor.20372.
    1. Stevenson S (1998) Enhancement of fracture healing with autogenous and allogeneic bone grafts. Clin Orthop Relat Res:S239–S246. 10.1177/1071100716649925
    1. Deng L, Li D, Yang Z, et al. Repair of the calvarial defect in goat model using magnesium-doped porous hydroxyapatite combined with recombinant human bone morphogenetic protein-2. Biomed Mater Eng. 2017;28:361–377.
    1. Yaman F, Dundar S, Cakmak O, et al. Guided bone regeneration with polyethylene membrane, zoledronic acid and hydroxiapatide bone graft in peri-implant bone defect: an experimental study. Biomed Res. 2017;28:2684–2688.
    1. Govender S, Csimma C, Genant HK, et al. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am. 2002;84–A:2123–2134. doi: 10.2106/00004623-200212000-00001.
    1. Conway JD, Shabtai L, Bauernschub A, Specht SC. BMP-7 versus BMP-2 for the treatment of long bone nonunion. Orthopedics. 2014;37:e1049–e1057. doi: 10.3928/01477447-20141124-50.
    1. Betz OB, Betz VM, Schröder C et al (2013) Repair of large segmental bone defects: BMP-2 gene activated muscle grafts vs. autologous bone grafting. BMC Biotechnol 13. 10.1186/1472-6750-13-65
    1. Giannoudis PV, Einhorn TA, Marsh D (2007) Fracture healing: the diamond concept. Injury 38. 10.1016/S0020-1383(08)70003-2
    1. Qu H, Guo W, Yang R et al (2015) Reconstruction of segmental bone defect of long bones after tumor resection by devitalized tumor-bearing bone. World J Surg Oncol:13. 10.1186/s12957-015-0694-3
    1. Wang Y, Jiang H, Deng Z et al (2017) Comparison of monolateral external fixation and internal fixation for skeletal stabilisation in the management of small tibial bone defects following successful treatment of chronic osteomyelitis. Biomed Res Int. 10.1155/2017/6250635
    1. Ismail HD, Kholinne E, Jusuf AA, Yulisa ND. Role of allogenic mesenchymal stem cells in the reconstruction of bone defect in rabbits. Med J Indones. 2014;23:9–14. doi: 10.13181/mji.v23i1.683.
    1. Lubis AMT, Sandhow L, Lubis VK, et al. Isolation and cultivation of mesenchymal stem cells from iliac crest bone marrow for further cartilage defect management. Acta Med Indones. 2011;43:178–184.
    1. Binkley JM, Stratford PW, Lott SA, Riddle DL. The lower extremity functional scale (LEFS): scale development, measurement properties, and clinical application. Phys Ther. 1999;79:371–383.
    1. Hudak PL, Amadio PC, Bombardier C. Development of an upper extremity outcome measure: the DASH (disabilities of the arm, shoulder, and hand) Am J Ind Med. 1996;29:602–608. doi: 10.1002/(SICI)1097-0274(199606)29:6<602::AID-AJIM4>;2-L.
    1. Tiedeman JJ, Lippiello L, Connolly JF, Strates BS. Quantitative roentgenographic densitometry for assessing fracture healing. Acta Orthop Scand. 1990;61:128–130. doi: 10.3109/17453679009006503.
    1. Dilogo IH, Kholinne E, Djaja YP, Yuyus Kusnadi LS. Osteogenic potency of human bone marrow mesenchymal stem cells from femoral atrophic non-union fracture site. J Clin Exp Investig. 2014;5:159–163. doi: 10.5799/ahinjs.01.2014.01.0382.
    1. El-Alfy B, Ali A. Management of segmental skeletal defects by the induced membrane technique. Indian J Orthop. 2015;49:643. doi: 10.4103/0019-5413.168757.
    1. Wang X, Luo F, Huang K, Xie Z. Induced membrane technique for the treatment of bone defects due to post-traumatic osteomyelitis. Bone Joint Res. 2016;5:101–105. doi: 10.1302/2046-3758.53.2000487.
    1. Fayaz HC, Giannoudis PV, Vrahas MS, et al. The role of stem cells in fracture healing and nonunion. Int Orthop. 2011;35:1587–1597. doi: 10.1007/s00264-011-1338-z.
    1. Marcacci M, Kon E, Moukhachev V, et al. Stem cells associated with macroporous bioceramics for long bone repair: 6-to 7-year outcome of a pilot clinical study. Tissue Eng. 2007;13:947–955. doi: 10.1089/ten.2006.0271.
    1. Quarto R, Mastrogiacomo M, Cancedda R, et al. Repair of large bone defects with the use of autologous bone marrow stromal cells. N Engl J Med. 2001;344:385–386. doi: 10.1056/NEJM200102013440516.
    1. Sulaiman SB, Keong TK, Cheng CH, Aminuddin Bin Saim RBHI. Tricalcium phosphate/hydroxyapatite (TCP-HA) bone scaffold as potential candidate for the formation of tissue engineered bone. Indian J Med Res. 2013;137:1093–1101.
    1. Ng AMH, Aminuddin BS, Tan KK, et al. Comparison of bioengineered human bone construct from four sources of osteogenic cells. J Orthop Sci. 2005;10:192–199. doi: 10.1007/s00776-004-0884-2.
    1. Bajada S, Harrison PE, Ashton BA, et al. Successful treatment of refractory tibial nonunion using calcium sulphate and bone marrow stromal cell implantation. J Bone Joint Surg (Br) 2007;89:1382–1386. doi: 10.1302/0301-620X.89B10.19103.
    1. Asadi-Eydivand M, Solati-Hashjin M, Shafiei SS et al (2016) Structure, properties, and in vitro behavior of heat-treated calcium sulfate scaffolds fabricated by 3D printing. PLoS One 11. 10.1371/journal.pone.0151216
    1. Malinin TI, Carpenter EM, Temple HT. Particulate bone allograft incorporation in regeneration of osseous defects; importance of particle sizes. Open Orthop J. 2007;1:19–24. doi: 10.2174/1874325000701010019.
    1. Sánchez F, Bolarm A, Molera P. Relationship between particle size and manufacturing processing and sintered characteristics of iron powders. Rev Latin Met Mat. 2003;23:35–40.
    1. Hernigou P, Poignard A, Beaujean F, Rouard H. Percutaneous autologous bone-marrow grafting for nonunions: influence of the number and concentration of progenitor cells. J Bone Joint Surg Am. 2005;87:1430–1437.
    1. Decambron A, Fournet A, Bensidhoum M, et al. Low-dose BMP-2 and MSC dual delivery onto coral scaffold for critical-size bone defect regeneration in sheep. J Orthop Res. 2017;35:2637–2645. doi: 10.1002/jor.23577.
    1. Niikura T, Hak DJ, Hari Reddi A. Global gene profiling reveals a downregulation of BMP gene expression in experimental atrophic nonunions compared to standard healing fractures. J Orthop Res. 2006;24:1463–1471. doi: 10.1002/jor.20182.
    1. El Bialy I, Jiskoot W, Reza Nejadnik M. Formulation, delivery and stability of bone morphogenetic proteins for effective bone regeneration. Pharm Res. 2017;34:1152–1170. doi: 10.1007/s11095-017-2147-x.
    1. Gao Y, Li C, Wang H, Fan G (2015) Acceleration of bone-defect repair by using A-W MGC loaded with BMP2 and triple point-mutant HIF1α-expressing BMSCs. J Orthop Surg Res 10. 10.1186/s13018-015-0219-3
    1. Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J. 2011;11:471–491. doi: 10.1016/j.spinee.2011.04.023.
    1. Little DG, McDonald M, Bransford R, et al. Manipulation of the anabolic and catabolic responses with OP-1 and zoledronic acid in a rat critical defect model. J Bone Miner Res. 2005;20:2044–2052. doi: 10.1359/JBMR.050712.
    1. Dilogo IH, Kamal AF, Gunawan B, Rawung RV. Autologous mesenchymal stem cell (MSCs) transplantation for critical-sized bone defect following a wide excision of osteofibrous dysplasia. Int J Surg Case Rep. 2015;17:106–111. doi: 10.1016/j.ijscr.2015.10.040.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere