Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Orthopaedic Surgery and Research
Published in: Journal of Orthopaedic Surgery and Research 1/2018

Open Access 01-12-2018 | Research article

Osseointegrative effect of rhBMP-2 covalently bound on a titan-plasma-spray-surface after modification with chromosulfuric acid in a large animal bone gap-healing model with the Göttingen minipig

Authors: Manuel Lingner, Roland Seidling, Lars Johannes Lehmann, Eckhard Mauermann, Udo Obertacke, Markus Ludwig Rupert Schwarz

Published in: Journal of Orthopaedic Surgery and Research | Issue 1/2018

Login to get access

Abstract

Background

Bone morphogenetic proteins play an important role as osseointegrative factors. It is used widely in orthopedic research and surgery to enhance the osseointegrative potential of implants, e.g., in spinal fusion or alveolar socket augmentation. The aim of the present study was to investigate the benefit of rhBMP-2 on a titan plasma spray (TPS) layer after a special modification with chromosulfuric acid (CSA) at different postoperative times, regarding osseoconduction and osseoinduction.

Methods

We allocated 27 Göttinger minipigs into three groups consisting of nine animals each. They received four dumbbell-shaped implants in the metaphyseal parts of the femora. The implants had a TPS surface with (CSA group) and without a CSA treatment (TPS group). The former received an additional layer of BMP-2 (BMP-2 group). For the assessment of osseointegration after healing periods of 4, 8, and 12 weeks, histomorphometry was applied to undecalcified specimens after staining according to Masson-Goldner. An intravital labeling with different fluorochromes was used in the gap model. A multivariable analysis with repeated measurement design was performed for statistical evaluation.

Results

We observed several statistical differences in a three-way ANOVA. The comparison between the BMP-2 and the TPS group (two-way ANOVA) showed statistically significant differences in terms of the osseoinduction (osteoid volume), and pronounced for the osseoconduction (bone and osteoid ongrowth), in favor of the BMP-2 group. In the pairwise comparison between BMP-2 and CSA (two-way ANOVA), no statistical significance occurred. The intravital staining with tetracycline, calcein green, and xylenol orange revealed no considerable differences between the groups.

Conclusion

BMP-2, covalently bound on a CSA-treated TPS surface, has positive effects on the osseointegration in the large animal bone gap-healing model over the observation period of 12 weeks.
Literature
1.
Beederman M, Lamplot JD, Nan G, Wang J, Liu X, Yin L. BMP signaling in mesenchymal stem cell differentiation and bone formation. Biomedical Science and Engineering. 2013;6:32–52.CrossRef
2.
3.
Jennissen H, Zumbrink T, Chatzinikolaidou M, Steppuhn J. Biocoating of implants with mediator molecules: surface enhancement of metals by treatment with chromosulfuric acid. Mat-wiss u Werkstofftech. 1999;30:838–45.CrossRef
4.
Jennissen HP, Luers S, Laub M. Hyperhydrophilic surfaces, the inverse lotus effect and imaginary contact angles. Biomed Tech (Berl). 2012:s1-D.
5.
Zurlinden KLM, Jennissen HP. Chemical functionalization of a hydroxyapatite based bone replacement material for the immobilization of proteins. Mat-wiss u Werkstofftech. 2005;36:820–7.CrossRef
6.
Chatzinikolaidou MZT, Jennissen HP. Stability of surface-enhanced ultrahydrophilic metals as a basis for bioactive rhBMP-2 surfaces. Mattwiss u Werkstofftech. 2003;34(12):1106–12.CrossRef
7.
Jennissen H. Method for immobilizing mediator molecules on inorganic and metal implant materials. PCT Patent WO9926674A2 (priority date Nov 24 1997); 1999. p. 1–29.
8.
Lichtinger TKMRT, Schürmann N, Oldenburg M, Wiemann M, Chatzinikolaidou M, Rumpf HM, Jennissen HP. Osseointegration of titanium implants by addition of recombinant bone morphogenetic protein 2 (rhBMP-2). Mat-wiss u Werkstofftech. 2001;32:937–41.CrossRef
9.
Voggenreiter G, Hartl K, Assenmacher S, Chatzinikolaidou M, Rumpf H, Jennissen H. Assesment of the biological activity of chemically immobilized rhBMP-2 on titanium surfaces in vivo. Mat-wiss u Werkstofftech. 2001;32:942–8.CrossRef
10.
Seidling R, Lehmann LJ, Lingner M, Mauermann E, Obertacke U, Schwarz MLR. Analysis of the osseointegrative force of a hyperhydrophilic and nanostructured surface refinement for TPS surfaces in a gap healing model with the Göttingen minipig. J Orthop Surg Res. 2016;11:119.
11.
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;11:471–91.CrossRefPubMed
12.
Rahbek O, Overgaard S, Jensen TB, Bendix K, Soballe K. Sealing effect of hydroxyapatite coating: a 12-month study in canines. Acta Orthop Scand. 2000;71:563–73.CrossRefPubMed
13.
Sumner DR, Turner TM, Urban RM, Turek T, Seeherman H, Wozney JM. Locally delivered rhBMP-2 enhances bone ingrowth and gap healing in a canine model. J Orthop Res. 2004;22:58–65.CrossRefPubMed
14.
Draenert Y, Draenert K. Gap healing of compact bone. Scan Electron Microsc. 1980;14:103–11.
15.
Johner R. Dependence of bone healing on defect size. Helv Chir Acta. 1972;39:409–11.PubMed
16.
Heino TJ, Alm JJ, Moritz N, Aro HT. Comparison of the osteogenic capacity of minipig and human bone marrow-derived mesenchymal stem cells. J Orthop Res. 2012;30:1019–25.CrossRefPubMed
17.
Mosekilde L, Kragstrup J, Richards A. Compressive strength, ash weight, and volume of vertebral trabecular bone in experimental fluorosis in pigs. Calcif Tissue Int. 1987;40:318–22.CrossRefPubMed
18.
Olerud S, Lorenzi GL. Triple fluorochrome labeling in bone formation and bone resorption. J Bone Joint Surg Am. 1970;52:274–8.CrossRefPubMed
19.
Aaron JE, Makins NB, Francis RM, Peacock M. Staining of the calcification front in human bone using contrasting fluorochromes in vitro. J Histochem Cytochem. 1984;32:1251–61.CrossRefPubMed
20.
Pautke C, Vogt S, Tischer T, Wexel G, Deppe H, Milz S, Schieker M, Kolk A. Polychrome labeling of bone with seven different fluorochromes: enhancing fluorochrome discrimination by spectral image analysis. Bone. 2005;37:441–5.CrossRefPubMed
21.
Schieker M, Pautke C, Reitz K, Hemraj I, Neth P, Mutschler W, Milz S. The use of four-colour immunofluorescence techniques to identify mesenchymal stem cells. J Anat. 2004;204:133–9.CrossRefPubMedPubMedCentral
22.
Dempster DW, Compston JE, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR, Parfitt AM. Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR histomorphometry nomenclature committee. J Bone Miner Res. 2013;28:2–17.CrossRefPubMedPubMedCentral
23.
Parfitt AM. Bone histomorphometry: standardization of nomenclature, symbols and units (summary of proposed system). Bone. 1988;9:67–9.CrossRefPubMed
24.
Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR. Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 1987;2:595–610.CrossRefPubMed
25.
Chatzinikolaidou M, Zumbrink T, Jennissen H. Stability of surface-enhanced ultrahydrophilic metals as a basis for bioactive rhBMP-2 surfaces. Mat-wiss- u Werkstofftech. 2003;33:720–7.CrossRef
26.
Chatzinikolaidou M, Lichtinger TK, Muller RT, Jennissen HP. Peri-implant reactivity and osteoinductive potential of immobilized rhBMP-2 on titanium carriers. Acta Biomater. 2010;6:4405–21.CrossRefPubMed
27.
Christensen BB. Autologous tissue transplantations for osteochondral repair. Dan Med J. 2016;63
28.
Schwarz M. Scintigraphic evaluation of bone formation in Göttingen minipigs. Scand J Lab Anim. 2010;37:8–13.
29.
Schwarz ML, Kowarsch M, Rose S, Becker K, Lenz T, Jani L. Effect of surface roughness, porosity, and a resorbable calcium phosphate coating on osseointegration of titanium in a minipig model. J Biomed Mater Res A. 2009;89:667–78.CrossRefPubMed
30.
Romeis B, Plenk HJ. Untersuchung des Binde- und Stützgewebes. In: Mikroskopische Technik. 17 edn; 1989.
31.
Donath K, Breuner G. A method for the study of undecalcified bones and teeth with attached soft tissues. The Sage-Schliff (sawing and grinding) technique. J Oral Pathol. 1982;11:318–26.CrossRefPubMed
32.
Romeis B, Böck P. Mikroskopische Technik. München: Urban und Fischer; 2001.
33.
Lehmann LJ, Werner A, Dinter DJ, Mauermann E, Seidling R, Brade J, Laub M, Luers S, Madenci S, Jennissen H, et al. Scintigraphic evaluation of rhBMP-2-biocoated implants reveals no ectopic bone formation. Biomed Pharmacother. 2011;65:63–8.CrossRefPubMed
34.
Oehse K. Validierung, Anpassung und Anwendung eines Makros zur Histomorphometrie in einem Spaltmodell. Studienarbeit. Universität Halle-Wittenberg: Fachbereich Ingenieurwissenschaften; 2005.
35.
T A, C J. Osteoinduction, osteoconduction and osseointegration. Eur Spine J. 2001;10(Suppl 2):S96–101.CrossRef
36.
Dimitriou R, Tsiridis E, Giannoudis PV. Current concepts of molecular aspects of bone healing. Injury. 2005;36:1392–404.CrossRefPubMed
37.
Fiedler J, Roderer G, Gunther KP, Brenner RE. BMP-2, BMP-4, and PDGF-bb stimulate chemotactic migration of primary human mesenchymal progenitor cells. J Cell Biochem. 2002;87:305–12.CrossRefPubMed
38.
Lind M. Growth factor stimulation of bone healing. Effects on osteoblasts, osteomies, and implants fixation. Acta Orthop Scand Suppl. 1998;283:2–37.PubMed
39.
Raida M, Heymann AC, Gunther C, Niederwieser D. Role of bone morphogenetic protein 2 in the crosstalk between endothelial progenitor cells and mesenchymal stem cells. Int J Mol Med. 2006;18:735–9.PubMed
40.
Becker J, Kirsch A, Schwarz F, Chatzinikolaidou M, Rothamel D, Lekovic V, Laub M, Jennissen HP. Bone apposition to titanium implants biocoated with recombinant human bone morphogenetic protein-2 (rhBMP-2). A pilot study in dogs. Clin Oral Investig. 2006;10:217–24.CrossRefPubMedPubMedCentral
41.
Chatzinikolaidou MLM, Rumpf H, Jennissen HP. Biocoating of electropolished and ultrahydrophilic titanium and cobalt chromium molybdenum alloy surfaces with proteins. Mat-wiss u Werkstofftech. 2002;33:720–7.CrossRef
42.
Wagner A, Sachse A, Keller M, Aurich M, Wetzel WD, Hortschansky P, Schmuck K, Lohmann M, Reime B, Metge J, et al. Qualitative evaluation of titanium implant integration into bone by diffraction enhanced imaging. Phys Med Biol. 2006;51:1313–24.CrossRefPubMed
43.
Schenk RK, Willenegger HR. Histology of primary bone healing: modifications and limits of recovery of gaps in relation to extent of the defect (author's transl). Unfallheilkunde. 1977;80:155–60.PubMed
44.
Schmalzried TP, Jasty M, Harris WH. Periprosthetic bone loss in total hip arthroplasty. Polyethylene wear debris and the concept of the effective joint space. J Bone Joint Surg Am. 1992;74:849–63.CrossRefPubMed
45.
Schliephake H, Aref A, Scharnweber D, Bierbaum S, Roessler S, Sewing A. Effect of immobilized bone morphogenic protein 2 coating of titanium implants on peri-implant bone formation. Clin Oral Implants Res. 2005;16:563–9.CrossRefPubMed
46.
Tressler MA, Richards JE, Sofianos D, Comrie FK, Kregor PJ, Obremskey WT. Bone morphogenetic protein-2 compared to autologous iliac crest bone graft in the treatment of long bone nonunion. Orthopedics. 2011;34:e877–84.CrossRefPubMed
47.
Schmidmaier G, Schwabe P, Wildemann B, Haas NP. Use of bone morphogenetic proteins for treatment of non-unions and future perspectives. Injury. 2007;38(Suppl 4):S35–41.CrossRefPubMed
48.
Wolfle JV, Fiedler J, Durselen L, Reichert J, Scharnweber D, Forster A, Schwenzer B, Reichel H, Ignatius A, Brenner RE. Improved anchorage of Ti6Al4V orthopaedic bone implants through oligonucleotide mediated immobilization of BMP-2 in osteoporotic rats. PLoS One. 2014;9:e86151.CrossRefPubMedPubMedCentral
49.
Schmidmaier G, Schwabe P, Strobel C, Wildemann B. Carrier systems and application of growth factors in orthopaedics. Injury. 2008;39(Suppl 2):S37–43.CrossRefPubMed
50.
51.
Aerssens J, Boonen S, Lowet G, Dequeker J. Interspecies differences in bone composition, density, and quality: potential implications for in vivo bone research. Endocrinology. 1998;139:663–70.CrossRefPubMed
52.
Pearce AI, Richards RG, Milz S, Schneider E, Pearce SG. Animal models for implant biomaterial research in bone: a review. Eur Cell Mater. 2007;13:1–10.CrossRefPubMed
53.
Christensen BB, Foldager CB, Olesen ML, Vingtoft L, Rolfing JH, Ringgaard S, Lind M. Experimental articular cartilage repair in the Gottingen minipig: the influence of multiple defects per knee. J Exp Orthop. 2015;2:13.CrossRefPubMedPubMedCentral
54.
Anderson CL, Whitaker MC. Heterotopic ossification associated with recombinant human bone morphogenetic protein-2 (infuse) in posterolateral lumbar spine fusion: a case report. Spine (Phila Pa 1976). 2012;37:E502–6.CrossRef
55.
Woo EJ. Recombinant human bone morphogenetic protein-2: adverse events reported to the manufacturer and user facility device experience database. Spine J. 2012;12:894–9.CrossRefPubMed
56.
Woo EJ. Adverse events reported after the use of recombinant human bone morphogenetic protein 2. J Oral Maxillofac Surg. 2012;70:765–7.CrossRefPubMed
57.
Woo EJ. Adverse events after recombinant human BMP2 in nonspinal orthopaedic procedures. Clin Orthop Relat Res. 2013;471:1707–11.CrossRefPubMed
58.
Fu R, Selph S, McDonagh M, Peterson K, Tiwari A, Chou R, Helfand M. Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spine fusion: a systematic review and meta-analysis. Ann Intern Med. 2013;158:890–902.CrossRefPubMed
59.
Simmonds MC, Brown JV, Heirs MK, Higgins JP, Mannion RJ, Rodgers MA, Stewart LA. Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data. Ann Intern Med. 2013;158:877–89.CrossRefPubMed
60.
Bramlage CP, Haupl T, Kaps C, Bramlage P, Muller GA, Strutz F. Bone morphogenetic proteins in the skeletal system. Z Rheumatol. 2005;64:416–22.CrossRefPubMed
Metadata
Title
Osseointegrative effect of rhBMP-2 covalently bound on a titan-plasma-spray-surface after modification with chromosulfuric acid in a large animal bone gap-healing model with the Göttingen minipig
Authors
Manuel Lingner
Roland Seidling
Lars Johannes Lehmann
Eckhard Mauermann
Udo Obertacke
Markus Ludwig Rupert Schwarz
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Orthopaedic Surgery and Research / Issue 1/2018
Electronic ISSN: 1749-799X
DOI
https://doi.org/10.1186/s13018-018-0915-x

Other articles of this Issue 1/2018

Journal of Orthopaedic Surgery and Research 1/2018 Go to the issue

Correction

Correction to: Outcomes of oblique lateral interbody fusion for degenerative lumbar disease in patients under or over 65 years of age

Research article

Factors associated with development of re-nonunion after primary revision in femoral shaft nonunion subsequent to failed intramedullary nailing

Research article

Clinical experience of debridement combined with resorbable bone graft substitute mixed with antibiotic in the treatment for infants with osteomyelitis

Research article

Collagen IX gene polymorphisms and lumbar disc degeneration: a systematic review and meta-analysis

Research article

Risk assessment and management of preoperative venous thromboembolism following femoral neck fracture

Research article

Unilateral percutaneous endoscopic debridement and drainage for lumbar infectious spondylitis