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Open Access 01-12-2018 | Study protocol

Evaluation of the clinical effectiveness of bioactive glass (S53P4) in the treatment of non-unions of the tibia and femur: study protocol of a randomized controlled non-inferiority trial

Authors: Michael C. Tanner, Raban Heller, Fabian Westhauser, Matthias Miska, Thomas Ferbert, Christian Fischer, Simone Gantz, Gerhard Schmidmaier, Patrick Haubruck

Published in: Trials | Issue 1/2018

Abstract

Background

Treatment of non-union remains challenging and often necessitates augmentation of the resulting defect with an autologous bone graft (ABG). ABG is limited in quantity and its harvesting incurs an additional surgical intervention leaving the risk for associated complications and morbidities. Therefore, artificial bone graft substitutes that might replace autologous bone are needed. S53P4-type bioactive glass (BaG) is a promising material which might be used as bone graft substitute due to its osteostimulative, conductive and antimicrobial properties. In this study, we plan to examine the clinical effectiveness of BaG as a bone graft substitute in Masquelet therapy in comparison with present standard Masquelet therapy using an ABG with tricalciumphosphate to fill the bone defect.

Methods/design

This randomized controlled, clinical non-inferiority trial will be carried out at the Department of Orthopedics and Traumatology at Heidelberg University. Patients who suffer from tibial or femoral non-unions with a segmental bone defect of 2–5 cm and who are receiving Masquelet treatment will be included in the study. The resulting bone defect will either be filled with autologous bone and tricalciumphosphate (control group, N = 25) or BaG (S53P4) (study group, N = 25). Subsequent to operative therapy, all patients will receive the same standardized follow-up procedures. The primary endpoint of the study is union achieved 1year after surgery.

Discussion

The results from the current study will help evaluate the clinical effectiveness of this promising biomaterial in non-union therapy. In addition, this randomized trial will help to identify potential benefits and limitations regarding the use of BaG in Masquelet therapy. Data from the study will increase the knowledge about BaG as a bone graft substitute as well as identify patients possibly benefiting from Masquelet therapy using BaG and those who are more likely to fail, thereby improving the quality of non-union treatment.

Trial registration

German Clinical Trials Register (DRKS), ID: DRKS00013882. Registered on 22 January 2018.

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Einhorn TA. The cell and molecular biology of fracture healing. Clin Orthop Relat Res. 1998:S7–21. http://www.ncbi.nlm.nih.gov/pubmed/9917622

Moghaddam A, Zimmermann G, Hammer K, Bruckner T, Grutzner PA, von Recum J. Cigarette smoking influences the clinical and occupational outcome of patients with tibial shaft fractures. Injury. 2011. doi: https://doi.org/10.1016/j.injury.2011.05.011.

Audige L, Griffin D, Bhandari M, Kellam J, Ruedi TP. Path analysis of factors for delayed healing and nonunion in 416 operatively treated tibial shaft fractures. Clin Orthop Relat Res. 2005;438:221–32. http://www.ncbi.nlm.nih.gov/pubmed/16131895 CrossRefPubMed

Calori GM, Mazza EL, Mazzola S, Colombo A, Giardina F, Romanò F, Colombo M. Non-unions. Clin Cases Miner Bone Metab. 2017;14(2):186-88. https://doi.org/10.11138/ccmbm/2017.14.1.186..

Metsemakers WJ, Claes G, Terryn PJ, Belmans A, Hoekstra H, Nijs S. Reamer-Irrigator-Aspirator bone graft harvesting for treatment of segmental bone loss: analysis of defect volume as independent risk factor for failure. Eur J Trauma Emerg Surg. 2017; https://doi.org/10.1007/s00068-017-0821-7.

Stafford PR, Norris BL. Reamer-irrigator-aspirator bone graft and bi Masquelet technique for segmental bone defect nonunions: a review of 25 cases. Injury. 2010;41(Suppl 2):S72–7. https://doi.org/10.1016/S0020-1383(10)70014-0.CrossRefPubMed

Bosemark P, Perdikouri C, Pelkonen M, Isaksson H, Tagil M. The Masquelet induced membrane technique with BMP and a synthetic scaffold can heal a rat femoral critical size defect. J Orthop Res. 2015;33:488–95. https://doi.org/10.1002/jor.22815.CrossRefPubMed

Karger C, Kishi T, Schneider L, Fitoussi F, Masquelet AC. Treatment of posttraumatic bone defects by the induced membrane technique. Orthop Traumatol Surg Res. 2012;98:97–102. https://doi.org/10.1016/j.otsr.2011.11.001.CrossRefPubMed

Masquelet AC, Begue T. The concept of induced membrane for reconstruction of long bone defects. Orthop Clin N Am. 2010;41:27–37. https://doi.org/10.1016/j.ocl.2009.07.011. table of contentsCrossRef

10.

Pelissier P, Masquelet AC, Bareille R, Pelissier SM, Amedee J. Induced membranes secrete growth factors including vascular and osteoinductive factors and could stimulate bone regeneration. J Orthop Res. 2004;22:73–9. https://doi.org/10.1016/s0736-0266(03)00165-7.CrossRefPubMed

11.

Moghaddam A, Zietzschmann S, Bruckner T, Schmidmaier G. Treatment of atrophic tibia non-unions according to ‘diamond concept’: results of one- and two-step treatment. Injury. 2015;46(Suppl 4):S39–50. https://doi.org/10.1016/s0020-1383(15)30017-6.CrossRefPubMed

12.

Schmidmaier G, Herrmann S, Green J, Weber T, Scharfenberger A, Haas NP, et al. Quantitative assessment of growth factors in reaming aspirate, iliac crest, and platelet preparation. Bone. 2006;39:1156–63. https://doi.org/10.1016/j.bone.2006.05.023.CrossRefPubMed

13.

Qvick LM, Ritter CA, Mutty CE, Rohrbacher BJ, Buyea CM, Anders MJ. Donor site morbidity with reamer-irrigator-aspirator (RIA) use for autogenous bone graft harvesting in a single centre 204 case series. Injury. 2013;44:1263–9. https://doi.org/10.1016/j.injury.2013.06.008.CrossRefPubMed

14.

Banwart JC, Asher MA, Hassanein RS. Iliac crest bone graft harvest donor site morbidity. A statistical evaluation. Spine (Phila Pa 1976). 1995;20:1055–60. https://www.ncbi.nlm.nih.gov/pubmed/7631235 CrossRef

15.

Boniver J, Humblet C, Delvenne P, Deman J, Rongy AM, Greimers R, et al. TNF-alpha and radiation-induced thymic lymphomas. Leukemia. 1992;6(Suppl 3):83S–4S. https://www.ncbi.nlm.nih.gov/pubmed/1602833.PubMed

16.

Cox G, Jones E, McGonagle D, Giannoudis PV. Reamer-irrigator-aspirator indications and clinical results: a systematic review. Int Orthop. 2011;35:951–6. https://doi.org/10.1007/s00264-010-1189-z.CrossRefPubMedPubMedCentral

17.

Bhandari M, Guyatt GH, Tong D, Adili A, Shaughnessy SG. Reamed versus nonreamed intramedullary nailing of lower extremity long bone fractures: a systematic overview and meta-analysis. J Orthop Trauma. 2000;14:2–9. https://www.ncbi.nlm.nih.gov/pubmed/10630795 CrossRefPubMed

18.

Blum B, Moseley J, Miller L, Richelsoph K, Haggard W. Measurement of bone morphogenetic proteins and other growth factors in demineralized bone matrix. Orthopedics. 2004;27:s161–5. https://www.ncbi.nlm.nih.gov/pubmed/14763551 PubMed

19.

Green J. History and development of suction-irrigation-reaming. Injury. 2010;41(Suppl 2):S24–31. https://doi.org/10.1016/S0020-1383(10)70005-X.CrossRefPubMed

20.

Hoegel F, Mueller CA, Peter R, Pfister U, Suedkamp NP. Bone debris: dead matter or vital osteoblasts. J Trauma. 2004;56:363–7. https://doi.org/10.1097/01.TA.0000047811.13196.02.CrossRefPubMed

21.

Sturmer KM. Measurement of intramedullary pressure in an animal experiment and propositions to reduce the pressure increase. Injury. 1993;24(Suppl 3):S7–21. https://www.ncbi.nlm.nih.gov/pubmed/8168880 CrossRefPubMed

22.

Westhauser F, Hollig M, Reible B, Xiao K, Schmidmaier G, Moghaddam A. Bone formation of human mesenchymal stem cells harvested from reaming debris is stimulated by low-dose bone morphogenetic protein-7 application in vivo. J Orthop. 2016;13:404–8. https://doi.org/10.1016/j.jor.2016.08.002.CrossRefPubMedPubMedCentral

23.

Reible B, Schmidmaier G, Prokscha M, Moghaddam A, Westhauser F. Continuous stimulation with differentiation factors is necessary to enhance osteogenic differentiation of human mesenchymal stem cells in-vitro. Growth Factors. 2017;35:179–88. https://doi.org/10.1080/08977194.2017.1401618.CrossRefPubMed

24.

Moghaddam A, Thaler B, Bruckner T, Tanner M, Schmidmaier G. Treatment of atrophic femoral non-unions according to the diamond concept: results of one- and two-step surgical procedure. J Orthop. 2017;14:123–33. https://doi.org/10.1016/j.jor.2016.10.003.CrossRefPubMed

25.

Akiho S, Kinoshita K, Matsunaga A, Ishii S, Seo H, Nishio J, et al. Incidence of delayed union one year after peri-acetabular osteotomy based on computed tomography. Int Orthop. 2017; https://doi.org/10.1007/s00264-017-3656-2.

26.

Fischer C, Frank M, Kunz P, Tanner M, Weber MA, Moghaddam A, et al. Dynamic contrast-enhanced ultrasound (CEUS) after open and minimally invasive locked plating of proximal humerus fractures. Injury. 2016;47:1725–31. https://doi.org/10.1016/j.injury.2016.05.005.CrossRefPubMed

27.

Haubruck P, Kammerer A, Korff S, Apitz P, Xiao K, Buchler A, et al. The treatment of nonunions with application of BMP-7 increases the expression pattern for angiogenic and inflammable cytokines: a matched pair analysis. J Inflamm Res. 2016;9:155–65. https://doi.org/10.2147/JIR.S110621.CrossRefPubMedPubMedCentral

28.

Moghaddam A, Breier L, Haubruck P, Bender D, Biglari B, Wentzensen A, et al. Non-unions treated with bone morphogenic protein 7: introducing the quantitative measurement of human serum cytokine levels as promising tool in evaluation of adjunct non-union therapy. J Inflamm (Lond). 2016;13:–3. https://doi.org/10.1186/s12950-016-0111-x.

29.

Fischer C, Nissen M, Schmidmaier G, Bruckner T, Kauczor HU, Weber MA. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for the prediction of non-union consolidation. Injury. 2017;48:357–63. https://doi.org/10.1016/j.injury.2017.01.021.CrossRefPubMed

30.

Fischer C, Preuss EM, Tanner M, Bruckner T, Krix M, Amarteifio E, et al. Dynamic contrast-enhanced sonography and dynamic contrast-enhanced magnetic resonance imaging for preoperative diagnosis of infected nonunions. J Ultrasound Med. 2016;35:933–42. https://doi.org/10.7863/ultra.15.06107.CrossRefPubMed

31.

De Long WG Jr, Einhorn TA, Koval K, McKee M, Smith W, Sanders R, et al. Bone grafts and bone graft substitutes in orthopaedic trauma surgery. A critical analysis. J Bone Joint Surg Am. 2007;89:649–58. https://doi.org/10.2106/JBJS.F.00465.CrossRefPubMed

32.

Pape HC, Evans A, Kobbe P. Autologous bone graft: properties and techniques. J Orthop Trauma. 2010;24(Suppl 1):S36–40. https://doi.org/10.1097/BOT.0b013e3181cec4a1.CrossRefPubMed

33.

van Gestel NA, Geurts J, Hulsen DJ, van Rietbergen B, Hofmann S, Arts JJ. Clinical applications of S53P4 bioactive glass in bone healing and osteomyelitic treatment: a literature review. Biomed Res Int. 2015;2015:684826. https://doi.org/10.1155/2015/684826.CrossRefPubMedPubMedCentral

34.

Westhauser F, Weis C, Prokscha M, Bittrich LA, Li W, Xiao K, et al. Three-dimensional polymer coated 45S5-type bioactive glass scaffolds seeded with human mesenchymal stem cells show bone formation in vivo. J Mater Sci Mater Med. 2016;27:119. https://doi.org/10.1007/s10856-016-5732-3.CrossRefPubMed

35.

Bortolin M, De Vecchi E, Romano CL, Toscano M, Mattina R, Drago L. Antibiofilm agents against MDR bacterial strains: is bioactive glass BAG-S53P4 also effective? J Antimicrob Chemother. 2016;71:123–7. https://doi.org/10.1093/jac/dkv327.CrossRefPubMed

36.

Efird J. Blocked randomization with randomly selected block sizes. Int J Environ Res Public Health. 2011;8:15–20. https://doi.org/10.3390/ijerph8010015.CrossRefPubMed

37.

Giannoudis PV, Einhorn TA, Schmidmaier G, Marsh D. The diamond concept—open questions. Injury. 2008;39(Suppl 2):S5–8. https://doi.org/10.1016/S0020-1383(08)70010-X.CrossRefPubMed

38.

Schmidmaier G, Moghaddam A. Long bone nonunion. Zeitschrift fur Orthopadie und Unfallchirurgie. 2015;153:659–74; quiz 75-6. https://doi.org/10.1055/s-0035-1558259.CrossRefPubMed

39.

Haubruck P, Ober J, Heller R, Miska M, Schmidmaier G, Tanner MC. Complications and risk management in the use of the reaming-irrigator-aspirator (RIA) system: RIA is a safe and reliable method in harvesting autologous bone graft. PLoS One. 2018;13:e0196051. https://doi.org/10.1371/journal.pone.0196051.CrossRefPubMedPubMedCentral

40.

Miska M, Findeisen S, Tanner M, Biglari B, Studier-Fischer S, Grutzner PA, et al. Treatment of nonunions in fractures of the humeral shaft according to the Diamond Concept. Bone Joint J. 2016;98-B:81–7. https://doi.org/10.1302/0301-620X.98B1.35682.CrossRefPubMed

41.

Team RC. R: A Language and Environment for Statistical Computing. 2015. https://www.R-project.org/.

42.

Wickham H. ggplot2: Elegant graphics for data analysis. New York: Springer-Verlag; 2009.CrossRef

43.

Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez JC, et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics. 2011;12:77. https://doi.org/10.1186/1471-2105-12-77.CrossRefPubMedPubMedCentral

44.

Heller RA, Raven TF, Swing T, Kunzmann K, Daniel V, Haubruck P, et al. CCL-2 as a possible early marker for remission after traumatic spinal cord injury. Spinal Cord. 2017;55:1002–9. https://doi.org/10.1038/sc.2017.69.CrossRefPubMed

45.

Moghaddam A, Sperl A, Heller R, Kunzmann K, Graeser V, Akbar M, et al. Elevated serum insulin-like growth factor 1 levels in patients with neurological remission after traumatic spinal cord injury. PLoS One. 2016;11:e0159764. https://doi.org/10.1371/journal.pone.0159764.CrossRefPubMedPubMedCentral

46.

Moghaddam A, Heller R, Daniel V, Swing T, Akbar M, Gerner HJ, et al. Exploratory study to suggest the possibility of MMP-8 and MMP-9 serum levels as early markers for remission after traumatic spinal cord injury. Spinal Cord. 2017;55:8–15. https://doi.org/10.1038/sc.2016.104.CrossRefPubMed

47.

Rahaman MN, Day DE, Bal BS, Fu Q, Jung SB, Bonewald LF, et al. Bioactive glass in tissue engineering. Acta Biomater. 2011;7:2355–73. https://doi.org/10.1016/j.actbio.2011.03.016.CrossRefPubMedPubMedCentral

48.

Westhauser F, Ciraldo F, Balasubramanian P, Senger AS, Schmidmaier G, Moghaddam A, et al. Micro-computed-tomography-guided analysis of in vitro structural modifications in two types of 45S5 bioactive glass based scaffolds. Materials (Basel). 2017;10 https://doi.org/10.3390/ma10121341.

49.

Vallier HA, Cureton BA, Patterson BM. Randomized, prospective comparison of plate versus intramedullary nail fixation for distal tibia shaft fractures. J Orthop Trauma. 2011;25:736–41. https://doi.org/10.1097/BOT.0b013e318213f709.CrossRefPubMed

50.

Chan AW, Tetzlaff JM, Gotzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586. https://doi.org/10.1136/bmj.e7586.CrossRefPubMedPubMedCentral

51.

Schulz KF, Altman DG, Moher D, Group C. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. Int J Surg. 2011;9:672–7. https://doi.org/10.1016/j.ijsu.2011.09.004.CrossRefPubMed

Title: Evaluation of the clinical effectiveness of bioactive glass (S53P4) in the treatment of non-unions of the tibia and femur: study protocol of a randomized controlled non-inferiority trial
Authors: Michael C. Tanner
Raban Heller
Fabian Westhauser
Matthias Miska
Thomas Ferbert
Christian Fischer
Simone Gantz
Gerhard Schmidmaier
Patrick Haubruck
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Trials / Issue 1/2018
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/s13063-018-2681-9

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Evaluation of the clinical effectiveness of bioactive glass (S53P4) in the treatment of non-unions of the tibia and femur: study protocol of a randomized controlled non-inferiority trial

Abstract

Background

Methods/design

Discussion

Trial registration

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods/design

Discussion

Trial registration

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