Evaluation of Biocompatibility of New Osteoplastic Xenomaterials Containing Zoledronic Acid and Strontium Ranelate

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Abstract

Background. The problem of improving the functional characteristics of implanted devices and materials used in traumatology and orthopedics is a topical issue.

Aim of the study — to study biocompatibility of bovine bone matrix xenomaterials modified by zoledronic acid and strontium ranelate when implanted into the bone defect cavity.

Methods. The study was performed on 24 male rabbits of the Soviet Chinchilla breed. Test blocks of bone matrix were implanted into the cavity of bone defects of the femur. Group 1 animals (n = 8, control group) were implanted with bone xenogenic material (Bio-Ost osteoplastic matrix). Group 2 animals (n = 8) were implanted with bone xenogenic material impregnated with zoledronic acid. Group 3 animals (n = 8) were implanted with bone xenogeneic material impregnated with strontium ranelate. Supercritical fluid extraction technology was used to purify the material and impregnate it with zoledronic acid and strontium ranelate. Radiological, pathomorphological, histological and laboratory (hematology and blood biochemistry) diagnostic methods were used to assess biocompatibility. Follow-up period was 182 days after implantation.

Results. It was found out that on the 182nd day after implantation the median area of the newly-formed bone tissue in the defect modeling area in Group 1 was 79%, in Group 2 — 0%, in Group 3 — 67%. In Group 2 the maximum area by this period was filled with connective tissue — 77%. Median relative area of implanted material fragments in Group 1 was 4%, in Group 2 — 23%, in Group 3 — 15%. No infection or material rejection was observed in animals of all groups. There were no signs of intoxication or prolonged systemic inflammatory reaction. Laboratory parameters did not change significantly over time. One animal in each group experienced one-time increase in C-reactive protein level against the background of leukocytosis. Two animals in Group 1 had a slight migration of implanted material under the skin, one animal developed arthritis of the knee joint.

Conclusion. Osteoplastic materials based on bovine bone xenomatrix and filled with zoledronic acid and strontium ranelate have acceptable values of biocompatibility including their safety profile.

About the authors

Maksim V. Stogov

National Ilizarov Medical Research Centre for Traumatology and Orthopedics

Author for correspondence.
Email: stogo_off@list.ru
ORCID iD: 0000-0001-8516-8571
SPIN-code: 9345-8300
Scopus Author ID: 26024482600
ResearcherId: N-5847-2018

Dr. Sci. (Biol.), Associate Professor

Russian Federation, 6, M. Ulyanova st., Kurgan, 640014

Olga V. Dyuryagina

National Ilizarov Medical Research Centre for Traumatology and Orthopedics

Email: diuriagina@mail.ru
ORCID iD: 0000-0001-9974-2204
SPIN-code: 8301-1475
Scopus Author ID: 56105040400
ResearcherId: AAB-3838-2021

Cand. Sci. (Vet.), head of laboratory

Russian Federation, 6, M. Ulyanova st., Kurgan, 640014

Tamara A. Silant'eva

National Ilizarov Medical Research Centre for Traumatology and Orthopedics

Email: tsyl@mail.ru
ORCID iD: 0000-0001-6405-8365
SPIN-code: 9942-7011
Scopus Author ID: 55543818800
ResearcherId: O-8458-2018

Cand. Sci. (Biol.), head of laboratory

Russian Federation, 6, M. Ulyanova st., Kurgan, 640014

Irina V. Shipitsyna

National Ilizarov Medical Research Centre for Traumatology and Orthopedics

Email: ivschimik@mail.ru
ORCID iD: 0000-0003-2012-3115
SPIN-code: 3039-5202
Scopus Author ID: 55891336600
ResearcherId: AAH-1004-2020

Cand. Sci. (Biol.), researcher

Russian Federation, 6, M. Ulyanova st., Kurgan, 640014

Elena A. Kireeva

National Ilizarov Medical Research Centre for Traumatology and Orthopedics

Email: ea_tkachuk@mail.ru
ORCID iD: 0000-0002-1006-5217
SPIN-code: 9598-0838
Scopus Author ID: 56716612200
ResearcherId: G-9986-2018

Cand. Sci. (Biol.), senior researcher

Russian Federation, 6, M. Ulyanova st., Kurgan, 640014

Mikhail A. Stepanov

National Ilizarov Medical Research Centre for Traumatology and Orthopedics

Email: m-stepanov@mail.ru
ORCID iD: 0000-0003-1331-8897
SPIN-code: 3325-8710
Scopus Author ID: 55302983500
ResearcherId: GZM-6775-2022

Cand. Sci. (Vet.), leading researcher

Russian Federation, 6, M. Ulyanova st., Kurgan, 640014

References

  1. Khlusov I.A., Porokhova E.D., Komarova E.G., Kazantseva E.A., Sharkeev Yu.P., Yurova K.A. et al. Scaffolds as carriers of drugs and biomolecules for bone tissue bioengineering. Tsitologiya. 2022;64(3):183-207. (In Russian). doi: 10.31857/S0041377122030051.
  2. Ghimire A., Song J. Anti-periprosthetic infection strategies: from implant surface topographical engineering to smart drug-releasing coatings. ACS Appl Mater Interfaces. 2021;13(18):20921-20937. doi: 10.1021/acsami.1c01389.
  3. He M., Huang Y., Xu H., Feng G., Liu L., Li Y. et al. Modification of polyetheretherketone implants: From enhancing bone integration to enabling multi-modal therapeutics. Acta Biomater. 2021;129:18-32. doi: 10.1016/j.actbio.2021.05.009.
  4. Lohberger B., Eck N., Glaenzer D., Kaltenegger H., Leithner A. Surface modifications of titanium aluminium vanadium improve biocompatibility and osteogenic differentiation potential. Materials (Basel). 2021;14(6):1574. doi: 10.3390/ma14061574.
  5. Borcherding K., Schmidmaier G., Hofmann G.O., Wildemann B. The rationale behind implant coatings to promote osteointegration, bone healing or regeneration. Injury. 2021;52 Suppl 2:S106-S111. doi: 10.1016/j.injury.2020.11.050.
  6. Hasan A., Byambaa B., Morshed M., Cheikh M.I., Shakoor R.A., Mustafy T. et al. Advances in osteobiologic materials for bone substitutes. J Tissue Eng Regen Med. 2018;12(6):1448-1468. doi: 10.1002/term.2677.
  7. Martin V., Bettencourt A. Bone regeneration: Biomaterials as local delivery systems with improved osteoinductive properties. Mater Sci Eng C Mater Biol Appl. 2018;82:363-371. doi: 10.1016/j.msec.2017.04.038.
  8. Stogov M.V., Smolentsev D.V., Kireeva E.A. Xenografts in Trauma and Orthopaedics (Analytical Review). Traumatology and Orthopedics of Russia. 2020;26(1):181-189. (In Russian). doi: 10.21823/2311-2905-2020-26-1-181-189.
  9. Amirazad H., Dadashpour M., Zarghami N. Application of decellularized bone matrix as a bioscaffold in bone tissue engineering. J Biol Eng. 2022;16(1):1. doi: 10.1186/s13036-021-00282-5.
  10. Zhang H., Yang L., Yang X.G., Wang F., Feng J.T., Hua K.C. et al. Demineralized bone matrix carriers and their clinical applications: an overview. Orthop Surg. 2019;11(5):725-737. doi: 10.1111/os.12509.
  11. Liu K.F., Chen R.F., Li Y.T., Lin Y.N., Hsieh D.J., Periasamy S. et al. Supercritical carbon dioxide decellularized bone matrix seeded with adipose-derived mesenchymal stem cells accelerated bone regeneration. Biomedicines. 2021;9(12):1825. doi: 10.3390/biomedicines9121825.
  12. Mattioli-Belmonte M., Montemurro F., Licini C., Iezzi I., Dicarlo M., Cerqueni G. et al. Cell-Free demineralized bone matrix for mesenchymal stem cells survival and colonization. Materials (Basel). 2019;12(9):1360. doi: 10.3390/ma12091360.
  13. Nie W., Wang Z., Cao J., Wang W., Guo Y., Zhang C. et al. Preliminary outcomes of the combination of demineralized bone matrix and platelet Rich plasma in the treatment of long bone non-unions. BMC Musculoskelet Disord. 2021;22(1):951. doi: 10.1186/s12891-021-04840-2.
  14. Jin Y.Z., Zheng G.B., Lee J.H., Han S.H. Comparison of demineralized bone matrix and hydroxyapatite as carriers of Escherichia coli recombinant human BMP-2. Biomater Res. 2021;25(1):25. doi: 10.1186/s40824-021-00225-7.
  15. He L.H., Zhang Z.Y., Zhang X., Xiao E., Liu M., Zhang Y. Osteoclasts may contribute bone substitute materials remodeling and bone formation in bone augmentation. Med Hypotheses. 2020;135:109438. doi: 10.1016/j.mehy.2019.109438.
  16. Zhu H., Blahnová V.H., Perale G., Xiao J., Betge F., Boniolo F. et al. Xeno-Hybrid bone graft releasing biomimetic proteins promotes osteogenic differentiation of hMSCs. Front Cell Dev Biol. 2020;8:619111. doi: 10.3389/fcell.2020.619111.
  17. Carvalho M.S., Cabral J.M.S., da Silva C.L., Vashishth D. Bone matrix non-collagenous proteins in tissue engineering: creating new bone by mimicking the extracellular matrix. Polymers (Basel). 2021;13(7):1095. doi: 10.3390/polym13071095.
  18. Leng Q., Liang Z., Lv Y. Demineralized bone matrix scaffold modified with mRNA derived from osteogenically pre-differentiated MSCs improves bone repair. Mater Sci Eng C Mater Biol Appl. 2021;119:111601. doi: 10.1016/j.msec.2020.111601.
  19. Rajendran A.K., Amirthalingam S., Hwang N.S. A brief review of mRNA therapeutics and delivery for bone tissue engineering. RSC Adv. 2022;12(15):8889-8900. doi: 10.1039/d2ra00713d.
  20. Stogov M.V., Dyuryagina O.V., Silanteva T.A. Kireeva E.A., Shipitsina I.V., Stepanov M.A. Preclinical evaluation of the efficacy and safety of a new osteoplastic material of xenogenic origin containing vancomycin or meropenem. Orthopaedic Genius. 2022;28(4):565-573. (In Russian). doi: 10.18019/1028-4427-2022-28-4-565-573.
  21. Cho H., Bucciarelli A., Kim W., Jeong Y., Kim N., Jung J. et al. Natural sources and applications of demineralized bone matrix in the field of bone and cartilage tissue engineering. Adv Exp Med Biol. 2020;1249:3-14. doi: 10.1007/978-981-15-3258-0_1.
  22. Govoni M., Lamparelli E.P., Ciardulli M.C., Santoro A., Oliviero A., Palazzo I. et al. Demineralized bone matrix paste formulated with biomimetic PLGA microcarriers for the vancomycin hydrochloride controlled delivery: Release profile, citotoxicity and efficacy against S. aureus. Int J Pharm. 2020;582:119322. doi: 10.1016/j.ijpharm.2020.119322.
  23. Zwolak P., Farei-Campagna J., Jentzsch T., von Rechenberg B., Werner C.M. Local effect of zoledronic acid on new bone formation in posterolateral spinal fusion with demineralized bone matrix in a murine model. Arch Orthop Trauma Surg. 2018;138(1):13-18. doi: 10.1007/s00402-017-2818-4.
  24. Parmaksiz M., Lalegül-Ülker Ö., Vurat M.T., Elçin A.E., Elçin Y.M. Magneto-sensitive decellularized bone matrix with or without low frequency-pulsed electromagnetic field exposure for the healing of a critical-size bone defect. Mater Sci Eng C Mater Biol Appl. 2021;124:112065. doi: 10.1016/j.msec.2021.112065.
  25. Ferrández-Montero A., Eguiluz A., Vazquez E., Guerrero J.D., Gonzalez Z., Sanchez-Herencia A.J. et al. Controlled SrR Delivery by the Incorporation of Mg Particles on Biodegradable PLA-Based Composites. Polymers (Basel). 2021;13(7):1061. doi: 10.3390/polym13071061.
  26. Küçüktürkmen B., Öz U.C., Toptaş M., Devrim B., Saka O.M., Bilgili H. et al. Development of zoledronic acid containing biomaterials for enhanced guided bone regeneration. J Pharm Sci. 2021;110(9):3200-3207. doi: 10.1016/j.xphs.2021.05.002.
  27. Raina D.B., Qayoom I., Larsson D., Zheng M.H., Kumar A., Isaksson H. et al. Guided tissue engineering for healing of cancellous and cortical bone using a combination of biomaterial based scaffolding and local bone active molecule delivery. Biomaterials. 2019;188:38-49. doi: 10.1016/j.biomaterials.2018.10.004.
  28. Patshina M.V., Voroshilin R.A., Osintsev A.M. Global biomaterials market: potential opportunities for raw materials of animal origin. Food processing: techniques and technology. 2021;51(2):270-289. (In Russian). doi: 10.21603/2074-9414-2021-2-270-289.
  29. Bracey D.N., Jinnah A.H., Willey J.S., Seyler T.M., Hutchinson I.D., Whitlock P.W. et al. Investigating the osteoinductive potential of a decellularized xenograft bone substitute. Cells Tissues Organs. 2019;207(2): 97-113. doi: 10.1159/000503280.
  30. Jinnah A.H., Whitlock P., Willey J.S., Danelson K., Kerr B.A., Hassan O.A. et al. Improved osseointegration using porcine xenograft compared to demineralized bone matrix for the treatment of critical defects in a small animal model. Xenotransplantation. 2021;28(2):e12662. doi: 10.1111/xen.12662.
  31. Erkhova L.V., Panov Yu.M., Gavryushenko N.S., Zaitsev V.V., Lukina Yu.S., Smolentsev D.V. et al. Supercritical Treatment of Xenogenic Bone Matrix in the Process of Manufacture of Implants for Osteosynthesis. Supercritical Fluids: Theory and Practice. 2019;14(4): 42-48. (In Russian). doi: 10.34984/SCFTP.2019.14.4.006.
  32. Baas J., Vestermark M., Jensen T., Bechtold J., Soballe K., Jakobsen T. Topical bisphosphonate augments fixation of bone-grafted hydroxyapatite coated implants, BMP-2 causes resorption-based decrease in bone. Bone. 2017;97:76-82. doi: 10.1016/j.bone.2017.01.007.
  33. Onyema O.O., Guo Y., Hata A., Kreisel D., Gelman A.E, Jacobsen E.A. et al. Deciphering the role of eosinophils in solid organ transplantation. Am J Transplant. 2020;20(4):924-930. doi: 10.1111/ajt.15660.
  34. Sørensen M., Barckman J., Bechtold J.E., Søballe K., Baas J. Preclinical evaluation of zoledronate to maintain bone allograft and improve implant fixation in revision joint replacement. J Bone Joint Surg Am. 2013;95(20):1862-1868. doi: 10.2106/JBJS.L.00641.
  35. Quarterman J.C., Phruttiwanichakun P., Fredericks D.C., Salem A.K. Zoledronic Acid Implant Coating Results in Local Medullary Bone Growth. Mol Pharm. 2022;19(12):4654-4664. doi: 10.1021/acs.molpharmaceut.2c00644.
  36. Weber M., Homm A., Müller S., Frey S., Amann K., Ries J. et al. Zoledronate causes a systemic shift of macrophage polarization towards M1 in vivo. Int J Mol Sci. 2021;22(3):1323. doi: 10.3390/ijms22031323.
  37. Borciani G., Ciapetti G., Vitale-Brovarone C., Baldini N. Strontium functionalization of biomaterials for bone tissue engineering purposes: a biological point of view. Materials (Basel). 2022;15(5):1724. doi: 10.3390/ma15051724.
  38. You J., Zhang Y., Zhou Y. Strontium functionalized in biomaterials for bone tissue engineering: a prominent role in osteoimmunomodulation. Front Bioeng Biotechnol. 2022;10:928799. doi: 10.3389/fbioe.2022.928799.
  39. Fillingham Y., Jacobs J. Bone grafts and their substitutes. Bone Joint J. 2016;98-B(1 Suppl A):6-9. doi: 10.1302/0301-620X.98B.36350.
  40. Rolvien T., Barbeck M., Wenisch S., Amling M., Krause M. Cellular mechanisms responsible for success and failure of bone substitute materials. Int J Mol Sci. 2018;19(10):2893. doi: 10.3390/ijms19102893.
  41. Cleemann R., Sorensen M., Bechtold J.E., Soballe K., Baas J. Healing in peri-implant gap with BMP-2 and systemic bisphosphonate is dependent on BMP-2 dose-A canine study. J Orthop Res. 2018;36(5):1406-1414. doi: 10.1002/jor.23766.
  42. Cleemann R., Sorensen M., West A., Soballe K., Bechtold J.E., Baas J. Augmentation of implant surfaces with BMP-2 in a revision setting: effects of local and systemic bisphosphonate. Bone Joint Res. 2021;10(8): 488-497. doi: 10.1302/2046-3758.108.BJR-2020-0280.R1.
  43. AbuMoussa S., Ruppert D.S., Lindsay C., Dahners L., Weinhold P. Local delivery of a zoledronate solution improves osseointegration of titanium implants in a rat distal femur model. J Orthop Res. 2018;36(12):3294-3298. doi: 10.1002/jor.24125.
  44. Kellesarian S.V., Subhi A.L., Harthi S., Saleh Binshabaib M., Javed F. Effect of local zoledronate delivery on osseointegration: a systematic review of preclinical studies. Acta Odontol Scand. 2017;75(7): 530-541. doi: 10.1080/00016357.2017.1350994.
  45. Butscheidt S., Moritz M., Gehrke T., Puschel K., Amling M., Hahn M. et al. Incorporation and remodeling of structural allografts in acetabular reconstruction: Multiscale, micro-morphological analysis of 13 pelvic explants. J Bone Joint Surg Am. 2018;100(16):1406-1415. doi: 10.2106/JBJS.17.01636.
  46. Wang W., Yeung K.W.K. Bone grafts and biomaterials substitutes for bone defect repair: A review. Bioact Mater. 2017;2(4):224-247. doi: 10.1016/j.bioactmat.2017.05.007.
  47. Sun J., Wang X., Fu C., Wang D., Bi Z. A crucial role of IL-17 in bone resorption during rejection of fresh bone xenotransplantation in rats. Cell Biochem Biophys. 2015;71(2):1043-1049. doi: 10.1007/s12013-014-0307-8.
  48. Marmor M.T., Matz J., McClellan R.T., Medam R., Miclau T. Use of osteobiologics for fracture management: the when, what, and how. Injury. 2021;52 Suppl 2: S35-S43. doi: 10.1016/j.injury.2021.01.030.
  49. Chiang C.W., Chen C.H., Manga Y.B., Huang S.C., Chao K.M., Jheng P.R. et al. Facilitated and controlled strontium ranelate delivery using GCS-HA nanocarriers embedded into PEGDA coupled with decortication driven spinal regeneration. Int J Nanomedicine. 2021;16:4209-4224. doi: 10.2147/IJN.S274461.

Supplementary files

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2. Fig. 1. X-rays of the implantation area on the day of the surgery: a — Group 1 (arrows indicate the implantation area); b — Group 2; c — Group 3

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3. Fig. 2. X-rays of the implantation area on the 182nd day after implantation: a — Group 1; b — Group 2; c — Group 3

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4. Fig. 3. Histostructure of the area of xenomaterial implantation on the border with the bone bed.

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