In Vivo Evaluation of Functionalized Biomimetic Hydroxyapatite for Local Delivery of Active Agents

Johan Forsgren, Ulrika Brohede, Sonya Piskounova, Albert Mihranyan, Sune Larsson, Maria Strømme, Håkan Engqvist

.

DOI: 10.4236/jbnb.2011.22019                

Abstract

This study was carried out to investigate the biological response in vivo to biomimetic hydroxyapatite implant coatings functionalized with bisphosphonates and bone morphogenetic proteins. The functionalization was carried out by a simple soaking procedure in the operating room immediately prior to surgery. Cylindrical titanium samples with and without coatings were implanted in the distal femoral epiphysis of sheep and retrieved after 6 weeks. The histological analysis proved that all samples were integrated well in the tissue with no signs of intolerance. Fewer osteoclasts were observed in the vicinity of bisphosphonate-functionalized samples and the bone was denser around these samples compared to the other samples. Samples functionalized with bone morphogenetic protein induced more bone/implant contact but showed a more inconsistent outcome with reduced bone density around the samples. This study demonstrates a simple method to functionalize implant coatings, which provides surgeons with an option of patient-specific functionalization of implants. The observed biological impact due to the delivery of active molecules from the coatings suggests that this strategy may also be employed to deliver antibiotics from similar coatings.

Keywords

Implant, titanium, hydroxyapatite, bisphosphonate, bone morphogenetic protein-2

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	[1] M. Dobzyniak, T. K. Fehring and S. Odum, “Early Failure in Total Hip Arthroplasty,” Clinical Orthopaedics and Related Research, Vol. 477, 2006, pp. 76-78. doi:10.1097/01.blo.0000203484.90711.52
[2]	[2] P. F. Sharkey, W. J. Hozack, R. H. Rothman, S. Shastri and S. M. Jacoby, “Why are Total Knee Arthroplasties Failing To- day,” Clinical Orthopaedics and Related Research, Vol. 404, 2002, pp. 7-13. doi:10.1097/00003086-200211000-00003
[3]	[3] S. Kurtz, K. Ong, E. Lau, F. Mowat and M. Halpern, “Projections of Primary and Revision Hip and Knee Arthroplasty in the United States from 2005 to 2030,” Journal of Bone and Joint Surgery-American Volume, Vol. 89A, No. 4, 2007, pp. 780-785. doi:10.2106/JBJS.F.00222
[4]	[4] K. A. Krackow and D. S. Hungerford, “Revision and Primary Hip and Knee Arthroplasty—A Cost-Analysis,” Clinical Orthopaedics and Related Research, Vol. 311, 1995, pp. 136-141.
[5]	[5] T. K. Fehring, S. Odum, W. L. Griffin, J. B. Mason and M. Nadaud, “Early Failures in Total Knee Arthroplasty,” Clinical Orthopaedics and Related Research, Vol. 392, 2001, pp. 315-318. doi:10.1097/00003086-200111000-00041
[6]	[6] A. J. Mangram, T. C. Horan, M. L. Pearson, L. C. Silver and W. R. Jarvis, “Guideline for Prevention of Surgical Site Infection, 1999,” Infection Control and Hospital Epidemi- ology, Vol. 20, No. 4, 1999, pp. 250-278. doi:10.1086/501620
[7]	[7] L. Y. Carreon, R. M. Puno, J. R. Dimar, S. D. Glassman and J. R. Johnson, “Perioperative Complications of Posterior Lumbar de Compression and Arthrodesis in Older Adults,” Journal of Bone and Joint Surgery-American Volume, Vol. 85A, No. 11, 2003, pp. 2089-2092.
[8]	[8] L. Pulido, E. Ghanem, A. Joshi, J. J. Purtill and J. Parvizi, “Periprosthetic Joint Infection: The Incidence, Timing, and Predisposing Factors,” Clinical Orthopaedics and Related Research, Vol. 466, No. 7, 2008, pp. 1710-1715. doi:10.1007/s11999-008-0209-4
[9]	[9] A. G. Gristina, “Implant Failure and the Immune-Incom petent Fibro-Inflammatory Zone,” Clinical Orthopaedics and Related Research, Vol. 298, 1994, pp. 106-118.
[10]	[10] D. Campoccia, L. Montanaro and C. R. Arciola “The Signifi- cance of Infection Related to Orthopedic Devices and Issues of Antibiotic Resistance,” Biomaterials, Vol. 27, No. 11, 2006, pp. 2331-2339. doi:10.1016/j.biomaterials.2005.11.044
[11]	[11] I. Landor, P. Vavrik, A. Sosna, D. Jahoda, H. Hahn and M. Daniel, “Hydroxyapatite Porous Coating and the Osteointe- gration of the Total Hip Replacement,” Archives of Rtho- paedic and Trauma Surgery, Vol. 127, No. 2, 2007, pp. 81-89. doi:10.1007/s00402-006-0235-1
[12]	[12] R. G. T. Geesink, “Osteoconductive Coatings for Total Joint Arthroplasty,” Clinical Orthopaedics and Related Research, Vol. 395, 2002, pp. 53-65. doi:10.1097/00003086-200202000-00007
[13]	[13] R. Z. LeGeros, J. P. LeGeros Hydroxyapatite and T. Kokubo, “Bioceramics and Their Clinical Applications.” Woodhead Publishing Limited, 2008.
[14]	[14] U. Brohede, J. Forsgren, S. Roos, A. Mihranyan, H. Engqvist and M. Str?mme, “Multifunctional Implant Coatings Providing Possibilities for Fast Antibiotics Loading with Subsequent Slow Release,” Journal of Materials Science-Materials in Medicine, Vol. 20, No. 9, 2009, pp. 1859-1867. doi:10.1007/s10856-009-3749-6
[15]	[15] J. ?berg, U. Brohede, A. Mihranyan, M. Str?mme and H. Engqvist, “Bisphosphonate Incorporation in Surgical Im- plant Coatings by Fast Loading and Co-Precipitation at Low Drug Concentrations,” Journal of Materials Science- Materials in Medicine, Vol. 20, No. 10, 2009, pp. 2053- 2061.
[16]	[16] S. Piskounova, J. Forsgren, U. Brohede, H. Engqvist and M. Str?mme, “In Vitro Characterization of Bioactive Titanium Dioxide/Hydroxyapatite Surfaces Functionalized with BMP-2,” Journal of Biomedical Materials Research Part B-Applied Biomaterials, Vol. 91B, No. 2, 2009, pp. 780- 787. doi:10.1002/jbm.b.31456
[17]	[17] U. Brohede, S. X. Zhao, F. Lindberg, A. Mihranyan, J. Forsgren, M. Str?mme, et al., “A Novel Graded Bioactive High Adhesion Implant Coating,” Applied Surface Science, Vol. 255, No. 17, 2009, pp. 7723-7728. doi:10.1016/j.apsusc.2009.04.149
[18]	[18] J. Forsgren, F. Svahn, T. Jarmar and H. Engqvist, “Forma- tionand Adhesion of Biomimetic Hydroxyapatite Deposited on Titanium Substrates,” Acta Biomaterialia, Vol. 3, No. 6, 2007, pp. 980-984. doi:10.1016/j.actbio.2007.03.006
[19]	[19] A. Mihranyan, J. Forsgren, M. Str?mme and H. Engqvist, “Assessing Surface Area Evolution during Biomimetic Growth of Hydroxyapatite Coatings,” Langmuir, Vol. 25, No. 3, 2009, pp. 1292-1295. doi:10.1021/la803520k
[20]	[20] K. Donath and G. Breuner, “A Method for the Study of Undecalcified Bones and Teeth with Attached Soft-Tiss ues-the Sage-Schliff (Sawing and Grinding) Technique,” Journal of Oral Pathology and Medicine, Vol. 11, No. 4, 1982, pp. 318-326. doi:10.1111/j.1600-0714.1982.tb00172.x
[21]	[21] E. Hay, J. Lemonnier, O. Fromigue, P. J. Marie, “Bone Morphogenetic Protein-2 Promotes Osteoblast Apoptosis through a Smad-Independent, Protein Kinase C-Dependent Signaling Pathway,” Journal of Biological Chemistry, Vol. 276, No. 31, 2001, pp. 29028-29036. doi:10.1074/jbc.M011265200
[22]	[22] E. Hay, J. Lemonnier, O. Fromigue, H. Guenou and P. J. Marie, “Bone Morphogenetic Protein Receptor IB Signaling Mediates Apoptosis Independently of Differen- tiation in Osteoblastic Cells,” Journal of Biological Chemistry, Vol. 279, No. 3, 2004, pp. 1650-1658.
[23]	[23] C. A. Luppen, E. Smith, L. Spevak, A. L. Boskey and B. Frenkel, “Bone Morphogenetic Protein-2 Restores Mineralization in Glucocorticoid-Inhibited MC3T3-E1 Os- teoblast Cultures,” Journal of Bone and Mineral Research, Vol. 18, No. 7, 2003, pp. 1186-1197. doi:10.1359/jbmr.2003.18.7.1186
[24]	[24] F. M. He, G. L. Yang, X. X. Wang and S. F. Zhao, “Bone Responses to Rough Titanium Implants Coated with Biomimetic Ca-P in Rabbit Tibia,” Journal of Biomedical Materials Research Part B-Applied Biomaterials, Vol. 90B, No. 2, 2009, pp. 857-863. doi:10.1002/jbm.b.31355
[25]	[25] F. Barrere, C. M. van der Valk, G. Meijer, R. A. J. Dalmeijer, K. de Groot and P. Layrolle, “Osteointegration of Bio- mimetic Apatite Coating Applied onto Dense and Porous Metal Implants in Femurs of Goats,” Journal of Biomedical Materials Research Part B-Applied Biomaterials, Vol. 67B, No. 1, 2003, pp. 655-665. doi:10.1002/jbm.b.10057