The intensity of subacute local biological effects after the implantation of ALBO-OS dental material based on hydroxyapatite and poly(lactide-co-glycolide): in vivo evaluation in rats

Veljko Ilić; Vladimir Biočanin; Đorđe Antonijević; Božana Petrović; Vukoman Jokanović; Dragan Ilić; Vesna Danilović; Nina Japundžić-Žigon; Smiljana Paraš; Jovana Milutinović; Sanja Milutinović-Smiljanić

doi:10.1515/bmt-2023-0640

Article

The intensity of subacute local biological effects after the implantation of ALBO-OS dental material based on hydroxyapatite and poly(lactide-co-glycolide): in vivo evaluation in rats

Veljko Ilić , Vladimir Biočanin , Đorđe Antonijević , Božana Petrović , Vukoman Jokanović , Dragan Ilić , Vesna Danilović , Nina Japundžić-Žigon , Smiljana Paraš , Jovana Milutinović and Sanja Milutinović-Smiljanić

Published/Copyright: July 15, 2024

Published by

Become an author with De Gruyter Brill

Submit Manuscript Author Information

From the journal Biomedical Engineering / Biomedizinische Technik Volume 69 Issue 6

Abstract

Objectives

This study aimed to evaluate the intensity of the subacute local biological effects after implantation and osseoconductive potential of novel hydroxyapatite-based bone substitute coated with poly (lactide-co-glycolide), named ALBO-OS, in comparison to Bio-Oss^®.

Methods

Fifteen male Wistar rats, randomly assigned into groups: 10, 20, and 30 days (n꞊5), were subcutaneously implanted with ALBO-OS and Bio-Oss^®. Furthermore, artificially made bone defects on both rat’s tibias were implanted with experimental materials. Unimplanted defects represented negative control. After the animals’ euthanizing, tissue samples were prepared and analyzed histologically and histomorphometrically.

Results

Normal healing of the epithelial tissue was observed, with no signs of infection or necrosis. Minimal vascular congestion was noted immediately around the graft, with no signs of tissue oedema, with a minimal capsule thickness. The applied material did not cause an inflammatory response (IR) of significant intensity, and 20 days after implantation, the IR was mainly assessed as minimal. The tibial specimen showed that ALBO-OS has good osseoconductive potential, similar to Bio-Oss^®, as well as low levels of acute and subacute inflammation.

Conclusions

The tested material exhibits satisfying biocompatibility, similar to Bio-Oss^®.

Keywords: biocompatibility; bone regeneration; hydroxyapatite; inflammation; poly(lactide-co-glycolide)

Corresponding author: Božana Petrović, Vinča Institute of Nuclear Sciences, National Institute of the Republic of Serbia, Belgrade University, Belgrade, Serbia, E-mail: bozana@vinca.rs

Funding source: Ministry of Science, Technological Development and Innovation of the Republic of Serbia

Award Identifier / Grant number: 451-03-68/2022-14/200129 and 451-03-66/2024-01/200

Research ethics: All experiments followed the EU Directives 2010/63/EU and the corresponding National legislation on Animal welfare act 2009/6/RS. All experimental procedures in this study conformed to The European Communities Council Directive of November 24, 1986 (86/609/EEC) and comply with the ARRIVE guidelines, and standards.
Informed consent: Not applicable.
Author contributions: VI was involved in experiments and drafting the manuscript. VB, ĐA and DI were involved in the design of the study, performed subcutaneous implantation and were included in interpretation of data. BP synthesized ALBO-OS scaffold and was involved in manuscript grafting. VJ was involved in the design of the study and revised it critically for important intellectual content. VD, NJŽ, SP and JM performed histological and histomorphometric analysis and interpreted and analyzed the data. SMS was involved in the conception of the study, drafting the manuscript and reviewed it critically. The authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: The authors state no conflict of interest.
Research funding: This work was supported by the Ministry of Science, Technological Development and Innovation of the Republic of Serbia (Grants No. 451-03-68/2022-14/200129 and 451-03-47/2023-01/200017).
Data availability: Not applicable.

References

1. al Ruhaimi, KA. Effect of calcium sulphate on the rate of osteogenesis in distracted bone. Int J Oral Maxillofac Surg 2001;30:228–33. https://doi.org/10.1054/ijom.2001.0048.Search in Google Scholar PubMed

2. Zhao, R, Yang, R, Cooper, PR, Khurshid, Z, Shavandi, A, Ratnayake, J. Bone grafts and substitutes in dentistry: a review of current trends and developments. Molecules 2021;26:3007. https://doi.org/10.3390/molecules26103007.Search in Google Scholar PubMed PubMed Central

3. Micic, M, Antonijevic, D, Milutinovic-Smiljanic, S, Trisic, D, Colovic, B, Kosanovic, D, et al.. Developing a novel resorptive hydroxyapatite-based bone substitute for over-critical size defect reconstruction: physicochemical and biological characterization and proof of concept in segmental rabbit’s ulna reconstruction. Biomed Tech 2020;65:491–505. https://doi.org/10.1515/bmt-2019-0218.Search in Google Scholar PubMed

4. Karadzic, I, Vucic, V, Jokanovic, V, Debeljak-Martacic, J, Markovic, D, Petrovic, S, et al.. Effects of novel hydroxyapatite-based 3D biomaterials on proliferation and osteoblastic differentiation of mesenchymal stem cells. J Biomed Mater Res A 2015;103A:350–7. https://doi.org/10.1002/jbm.a.35180.Search in Google Scholar PubMed

5. Matassi, F, Nistri, L, Chicon Paez, D, Innocenti, M. New biomaterials for bone regeneration. Clin Cases Miner Bone Metab 2011;8:21–4.Search in Google Scholar

6. Liu, Q, Douglas, T, Zamponi, C, Becker, ST, Sherry, E, Sivananthan, S, et al.. Comparison of in vitro biocompatibility of NanoBones and BioOss for human osteoblasts. Clin Oral Impl Res 2011;22:1259–64. https://doi.org/10.1111/j.1600-0501.2010.02100.x.Search in Google Scholar PubMed

7. Duda, M, Pajak, J. The issue of bioresorption of the Bio-Oss xenogeneic bone substitute in bone defects. Ann Univ Mariae Curie Sklodowska 2004;59:269–77.Search in Google Scholar

8. Li, JJ, Kaplan, DL, Zreiqat, H. Scaffold-based regeneration of skeletal tissues to meet clinical challenge. J Mater Chem B 2014;2:7272–306. https://doi.org/10.1039/c4tb01073f.Search in Google Scholar PubMed

9. Jokanovic, V, Colovic, B, Markovic, D, Petrovic, M, Jokanovic, M, Milosavljevic, P, et al.. In Vivo investigation of HAP+PLGA scaffold based on hydroxyapatite and PLGA. J Nanomater 2016;2016:3948768.10.1155/2016/3948768Search in Google Scholar

10. Milutinovic-Smiljanic, S, Antonijevic, D, Jokanovic, V, Micic, M, Biocanin, V, Sjerobabin, N, et al.. The influence of various coatings of hydroxyapatite bone carrier on the success of bone regeneration in rabbit calvarial defects: histomorphometric and histological analysis. Vojnosanit Pregl 2022;79:1025–34. https://doi.org/10.2298/vsp210513072m.Search in Google Scholar

11. Jokanovic, V, Colovic, B, Markovic, D, Petrovic, M, Soldatovic, I, Antonijevic, D, et al.. Extraordinary biological properties of a new calcium hydroxyapatite/poly(lactide-co-glycolide)-based scaffold confirmed by in vivo investigation. Biomed Tech 2017;62:295–306. https://doi.org/10.1515/bmt-2015-0164.Search in Google Scholar PubMed

12. Ghanaati, S, Barbeck, M, Willershausen, I, Thimm, B, Stuebinger, S, Kortinskas, T, et al.. Nanocrystalline hydroxyapatite bone substitute leads to sufficient bone tissue formation already after 3 months: histological and histomorphometrical analysis 3 and 6 months following human sinus cavity augmentation. Clin Implant Dent Relat Res 2013;15:883–92. https://doi.org/10.1111/j.1708-8208.2011.00433.x.Search in Google Scholar PubMed

13. Arcos, D, Vallet-Regi, M. Substituted hydroxyapatite coatings of bone implants. J Mater Chem B 2020;8:1781–800. https://doi.org/10.1039/c9tb02710f.Search in Google Scholar PubMed PubMed Central

14. Khan, A, Waqar, K, Shafique, A, Irfan, R, Gul, A. Chapter 18: in vitro and in vivo animal models: the engineering towards understanding human diseases and therapeutic interventions. In: Barh, D, Azevedo, V, editors. Omics Technologies and Bio-Engineering. India: Academic Press; 2018:431–48 pp.10.1016/B978-0-12-804659-3.00018-XSearch in Google Scholar

15. Mukherjee, P, Roy, S, Ghosh, D, Nandi, SK. Role of animal models in biomedical research: a review. Lab Anim Res 2022;38:18. https://doi.org/10.1186/s42826-022-00128-1.Search in Google Scholar PubMed PubMed Central

16. Frame, JW. A convenient animal model for testing bone substitute materials. J Oral Surg 1980;38:176–80.Search in Google Scholar

17. Wancket, LM. Animal models for evaluation of bone implants and devices: comparative bone structure and common model uses. Vet Pathol 2015;52:842–50. https://doi.org/10.1177/0300985815593124.Search in Google Scholar PubMed

18. Stevanovic, M, Selakovic, D, Vasovic, M, Ljujic, B, Zivanovic, S, Papic, M, et al.. Comparison of hydroxyapatite/poly(lactide-co-glycolide) and hydroxyapatite/polyethyleneimine composite scaffolds in bone regeneration of swine mandibular critical size defects: in vivo study. Molecules 2022;27:1694. https://doi.org/10.3390/molecules27051694.Search in Google Scholar PubMed PubMed Central

19. Radhakrishnan, N, Veeraragavan, V. Chapter 8: natural products as anti-inflammatory agents. In: Rahman, A, editor. Studies in natural products chemistry. Amsterdam: Elsevier; 2020, vol 67:269–306 pp.10.1016/B978-0-12-819483-6.00008-4Search in Google Scholar

20. Pahwa, R, Goyal, A, Jialal, I. Chronic inflammation. In: StatPearls [Internet]. Treasure Island, FL: StatPearls; 2022.Search in Google Scholar

21. Thomas, MV, Puleo, DA. Infection, inflammation, and bone regeneration: a paradoxical relationship. J Dent Res 2011;90:1052–61. https://doi.org/10.1177/0022034510393967.Search in Google Scholar PubMed PubMed Central

22. International Organization for Standardization. Biological evaluation of medical devices – Part 6: tests for local effects after implantation. Switzerland, Geneva: International Organization for Standardization; 2016. ISO 10993.Search in Google Scholar

23. Kilkenny, C, Browne, W, Cuthill, IC, Emerson, M, Altman, DG. NC3Rs reporting guidelines working group. Br J Pharmacol 2010;160:1577–9. https://doi.org/10.1111/j.1476-5381.2010.00872.x.Search in Google Scholar PubMed PubMed Central

24. McGrath, JC, Lilley, E. Implementing guidelines on reporting research using animals (ARRIVE, etc.): new requirements for publication in BJP. Br J Pharmacol 2015;172:3189–93. https://doi.org/10.1111/bph.12955.Search in Google Scholar PubMed PubMed Central

25. American National Standard Institute/American Dental Association. Biological evaluation of medical devices – Part 6: test for local effect after implantation. Washington, DC: American National Standard Institute; 1995.Search in Google Scholar

26. American National Standard Institute/American Dental Association. Document No. 41 for recommended standard practices for biological evaluation of dental materials. Washington, DC: American National Standard Institute; 1998.Search in Google Scholar

27. Kubiak, BD, Albert, SP, Gatto, LA, Snyder, KP, Maier, KG, Vieau, CJ, et al.. Peritoneal negative pressure therapy prevents multiple organ injury in a chronic porcine sepsis and ischemia/reperfusion model. Shock 2010;34:525–34. https://doi.org/10.1097/shk.0b013e3181e14cd2.Search in Google Scholar PubMed

28. Lindner, C, PrÖhl, A, Abels, M, Löffler, T, Batinic, M, Jung, O, et al.. Specialized histological and histomorphometrical analytical methods for biocompatibility testing of biomaterials for maxillofacial surgery in (pre-) clinical studies. Vivo 2020;34:3137–52. https://doi.org/10.21873/invivo.12148.Search in Google Scholar PubMed PubMed Central

29. Barbeck, M, Udeabor, SE, Lorenz, J, Kubesch, A, Choukroun, J, Sader, RA, et al.. Induction of multinucleated giant cells in response to small sized bovine bone substitute (Bio-Oss TM) results in an enhanced early implantation bed vascularization. Ann Maxillofac Surg 2014;4:150–7. https://doi.org/10.4103/2231-0746.147106.Search in Google Scholar PubMed PubMed Central

30. Ghanaati, S, Barbeck, M, Detsch, R, Deisinger, U, Hilbig, U, Rausch, V, et al.. The chemical composition of synthetic bone substitutes influences tissue reactions in vivo: histological and histomorphometrical analysis of the cellular inflammatory response to hydroxyapatite, beta-tricalcium phosphate and biphasic calcium phosphate ceramics. Biomed Mater 2012;7:015005. https://doi.org/10.1088/1748-6041/7/1/015005.Search in Google Scholar PubMed

31. Ghanaati, S, Orth, C, Barbeck, M, Willershausen, I, Th imm, BW, Booms, P, et al.. Histological and histomorphometrical analysis of a silica matrix embedded nanocrystalline hydroxyapatite bone substitute using the subcutaneous implantation model in Wistar rats. Biomed Mater 2010;5:035005. https://doi.org/10.1088/1748-6041/5/3/035005.Search in Google Scholar PubMed

32. Chen, Z, Wu, C, Gu, W, Klein, T, Crawford, R, Xiao, Y. Osteogenic differentiation of bone marrow MSCs phosphate stimulating macrophages via MBP2 signalling pathway. Biomater 2014;35:1507–18. https://doi.org/10.1016/j.biomaterials.2013.11.014.Search in Google Scholar PubMed

33. Champagne, CM, Takebe, J, Offenbacher, S, Cooper, LF. Macrophage cell produce osteoinductive signals that include bone morphogenetic protein-2. Bone 2002;30:26–31. https://doi.org/10.1016/s8756-3282(01)00638-x.Search in Google Scholar PubMed

34. Freytes, DO, Kang, JW, Marcos-Campos, I, Vunjak-Novakovic, G. Macrophages modulate the viability and growth of human mesenchymal stem cells. J Cell Biochem 2013;114:220–9. https://doi.org/10.1002/jcb.24357.Search in Google Scholar PubMed

35. Kolacykowska, E, Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 2013;13:159–75. https://doi.org/10.1038/nri3399.Search in Google Scholar PubMed

36. Skaper, SD, Facci, L, Giusti, P. Mast cells, glia and neuroinflammation: partners in crime? Immunology 2014;141:314–57. https://doi.org/10.1111/imm.12170.Search in Google Scholar PubMed PubMed Central

37. Konnecke, I, Serra, A, Khassawna, TE, Schlundt, C, Schell, H, Hauser, A, et al.. T and B cells participate in bone repair by infiltrating the fracture callus in a two-wave fashion. Bone 2014;64:155–65. https://doi.org/10.1016/j.bone.2014.03.052.Search in Google Scholar PubMed

38. Lindner, C, Alkildani, S, Stojanovic, S, Najman, S, Jung, O, Barbeck, M. In vivo biocompatibility analysis of a novel barrier membrane based on bovine dermis-derived collagen for guided bone regeneration (GBR). Membranes 2022;12:378. https://doi.org/10.3390/membranes12040378.Search in Google Scholar PubMed PubMed Central

39. Lih, E, Park, W, Park, KW, Chun, SY, Kim, H, Joung, YK, et al.. A bioinspired scaffold with anti-inflammatory magnesium hydroxide and decellularized extracellular matrix for renal tissue regeneration. ACS Cent Sci 2019;5:458–67. https://doi.org/10.1021/acscentsci.8b00812.Search in Google Scholar PubMed PubMed Central

40. Go, EJ, Kang, EY, Lee, SK, Park, S, Kim, JH, Park, W, et al.. An osteoconductive PLGA scaffold with bioactive β-TCP and anti-inflammatory Mg(OH)2 to improve in vivo bone regeneration. Biomater Sci 2020;8:937–48. https://doi.org/10.1039/c9bm01864f.Search in Google Scholar PubMed

41. Julier, Z, Park, AJ, Briquez, PS, Martino, MM. Promoting tissue regeneration by modulating the immune system. Acta Biomater 2017;53:13–28. https://doi.org/10.1016/j.actbio.2017.01.056.Search in Google Scholar PubMed

42. Baker, DG. Natural pathogens of laboratory mice, rats, and rabbits and their effects on research. Clin Microbiol Rev 1998;11:231–66. https://doi.org/10.1128/cmr.11.2.231.Search in Google Scholar

43. Lee, S, Hyunmin, C, June, S, Moon-Kyu, C, Young-Bum, P. Comparative study of recombinant human bone morphogenetic protein-2 carriers in rat subcutaneous tissues: pilot study. Tissue Eng Regener Med 2015;12:138–46. https://doi.org/10.1007/s13770-015-0437-0.Search in Google Scholar

44. van Houdt, CIA, Ulrich, DJO, Jansen, JA, van den Beucken, JJJP. The performance of CPC/PLGA and Bio-Oss® for bone regeneration in healthy and osteoporotic rats. J Biomed Mater Res B Appl Biomater 2018;106:131–42. https://doi.org/10.1002/jbm.b.33801.Search in Google Scholar PubMed

45. Stavropoulos, A, Kostopoulos, L, Nyengaard, JR, Karring, T. Deproteinized bovine bone (Bio-Oss) and bioactive glass (Biogran) arrest bone formation when used as an adjunct to guided tissue regeneration (GTR): an experimental study in the rat. J Clin Periodontol 2003;30:636–43. https://doi.org/10.1034/j.1600-051x.2003.00093.x.Search in Google Scholar PubMed

46. Stavropoulos, A, Kostopoulos, L, Nyengaard, JR, Karring, T. Fate of bone formed by guided tissue regeneration with or without grafting of Bio-Oss or Biogran. An experimental study in the rat. J Clin Periodontol 2004;31:30–9. https://doi.org/10.1111/j.0303-6979.2004.00434.x.Search in Google Scholar PubMed

47. Chu, CR, Szczodry, M, Bruno, S. Animal models for cartilage regeneration and repair. Tissue Eng Part B 2010;16:105–15. https://doi.org/10.1089/ten.teb.2009.0452.Search in Google Scholar PubMed PubMed Central

48. Muschler, GF, Raut, VP, Patterson, TE, Wenke, JC, Hollinger, JO. The design and use of animal models for translational research in bone tissue engineering and regenerative medicine. Tissue Eng Part B 2010;16:123–45. https://doi.org/10.1089/ten.teb.2009.0658.Search in Google Scholar

49. Schwartz, Z, Doukarsky-Marx, T, Nasatzky, E, Goultschin, J, Rainly, DM, Greenspan, DC, et al.. Differential effects of bone graft substitutes on regeneration of bone marrow. Clin Oral Implants Res 2008;19:1233–45. https://doi.org/10.1111/j.1600-0501.2008.01582.x.Search in Google Scholar PubMed

50. Paraš, S, Janković, O, Trišić, D, Čolović, B, Mitrović‐Ajtić, O, Dekić, R, et al.. Influence of nanostructured calcium aluminate and calcium silicate on the liver: histological and unbiased stereological analysis. Int Endod J 2019;52:1162–72. https://doi.org/10.1111/iej.13105.Search in Google Scholar PubMed

Received: 2023-12-11

Accepted: 2024-06-24

Published Online: 2024-07-15

Published in Print: 2024-12-17

You are currently not able to access this content.

Articles in the same Issue

https://doi.org/10.1515/bmt-2023-0640

Keywords for this article

biocompatibility; bone regeneration; hydroxyapatite; inflammation; poly(lactide-co-glycolide)