Skip to main content
Log in

Preparation and performance of porous hydroxyapatite/poly(lactic-co-glycolic acid) drug-loaded microsphere scaffolds for gentamicin sulfate delivery

  • Materials for life sciences
  • Published:
Journal of Materials Science Aims and scope Submit manuscript

Abstract

The prevention/treatment of osteomyelitis infection by combining the local antibiotic delivery system with the bone regeneration scaffold can effectively overcome the drawbacks of systemic antibiotic administration and realize the full cycle control of drug release. Herein, by introducing sodium carboxymethyl cellulose (SCMC) cross-linking agent to improve the binding force of poly(lactic-co-glycolic acid) (PLGA) microspheres and porous hydroxyapatite (HAp) bone scaffold. The porous HAp/PLGA drug-loaded microsphere bone scaffold for gentamicin sulfate (GS) delivery was successfully prepared. The optimal preparation parameters, drug release characteristics, SCMC enhancement mechanism, antibacterial properties and bone cell activity of porous HAp/PLGA drug-loaded microsphere bone scaffolds were comprehensively investigated. The results showed that the 0.1% SCMC-modified porous HAp/PLGA drug-loaded microsphere bone scaffold has a cumulative drug release of 45.0 ± 0.90% on the first day, which is about 20% lower than that of pure PLGA drug-loaded microspheres. Moreover, its drug release can be sustained and stably released for more than 17 d, which is attributed to the enhancement of the binding force between the microspheres and HAp by SCMC (combination for more than 3 weeks). Meanwhile, the diameter of the antibacterial ring expanded from the initial 10 ± 0.50 to 28 ± 1.2 mm after 14 d, which also indicated the sustained and stable release of GS. Alamar Blue analysis results showed that 0.1% SCMC-modified composite bone scaffold is beneficial to the proliferation activity of bone cells, and its 14 day activity increased by 20%. The above results indicate that the SCMC-modified composite bone scaffold has the potential to treat/prevent osteomyelitis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11

Similar content being viewed by others

References

  1. Muthukrishnan G, Masters EA, Daiss JL, Schwarz EM (2019) Mechanisms of immune evasion and bone tissue colonization that make S. aureus the primary pathogen in osteomyelitis. Curr Osteoporos Rep 17:395–404. https://doi.org/10.1007/s11914-019-00548-4

    Article  Google Scholar 

  2. Zhang J, Wei Q, Zhou H et al (2020) Sustainable release of vancomycin from micro-arc oxidised 3D-printed porous Ti6Al4V for treating methicillin-resistant S. aureus bone infection and enhancing osteogenesis in a rabbit tibia osteomyelitis model. Biomater Sci 8:3106–3115. https://doi.org/10.1039/C9BM01968E

    Article  CAS  Google Scholar 

  3. Mestres G, Fernandez-Yague MA, Pastorino D, Montufar EB, Canal C, Manzanares-Céspedes MC, Ginebra MP (2019) In vivo efficiency of antimicrobial inorganic bone grafts in osteomyelitis treatments. Mater Sci Eng C 97:84–95. https://doi.org/10.1016/j.msec.2018.11.064

    Article  CAS  Google Scholar 

  4. Diefenbeck M, Schrader C, Gras F et al (2016) Gentamicin coating of plasma chemical oxidized titanium alloy prevents implant-related osteomyelitis in rats. Biomaterials 101:156–164. https://doi.org/10.1016/j.biomaterials.2016.05.039

    Article  CAS  Google Scholar 

  5. Ryan EJ, Ryan AJ, González-Vázquez A et al (2019) Collagen scaffolds functionalised with copper-eluting bioactive glass reduce infection and enhance osteogenesis and angiogenesis both in vitro and in vivo. Biomaterials 197:405–416. https://doi.org/10.1016/j.biomaterials.2019.01.031

    Article  CAS  Google Scholar 

  6. Dhal C, Mishra R (2020) In vitro and in vivo evaluation of gentamicin sulphate-loaded PLGA nanoparticle-based film for the treatment of surgical site infection. Drug Deliv Transl Res 10:1032–1043. https://doi.org/10.1007/s13346-020-00730-7

    Article  CAS  Google Scholar 

  7. Dorati R, DeTrizio A, Genta I, Grisoli P, Merelli A, Tomasi C, Conti B (2016) An experimental design approach to the preparation of pegylated polylactide-co-glicolide gentamicin loaded microparticles for local antibiotic delivery. Mater Sci Eng C 58:909–917. https://doi.org/10.1016/j.msec.2015.09.053

    Article  CAS  Google Scholar 

  8. McKinney W, Yonovitz A, Smolensky MH (2015) Circadian variation of gentamicin toxicity in rats. Laryngoscope 125:252–256. https://doi.org/10.1002/lary.25116

    Article  CAS  Google Scholar 

  9. Hahn H, Salt AN, Schumacher U, Plontke SK (2013) Gentamicin concentration gradients in scala tympani perilymph following systemic applications. Audiol Neurotol 18:383–391. https://doi.org/10.1159/000355283

    Article  CAS  Google Scholar 

  10. Nandi SK, Bandyopadhyay S, Das P, Samanta I, Mukherjee P, Roy S, Kundu B (2016) Understanding osteomyelitis and its treatment through local drug delivery system. Biotechnol Adv 34:1305–1317. https://doi.org/10.1016/j.biotechadv.2016.09.005

    Article  CAS  Google Scholar 

  11. Ji K, Wang YN, Wei QH, Zhang K, Jiang AG, Rao YW, Cai XX (2018) Application of 3D printing technology in bone tissue engineering. Bio-Design Manuf 1:203–210. https://doi.org/10.1007/s42242-018-0021-2

    Article  Google Scholar 

  12. Kim H-W, Kim Y-J (2021) Fabrication of strontium-substituted hydroxyapatite scaffolds using 3D printing for enhanced bone regeneration. J Mater Sci 56:1673–1684. https://doi.org/10.1007/s10853-020-05391-y

    Article  CAS  Google Scholar 

  13. Loca D, Sokolova M, Locs J, Smirnova A, Irbe Z (2015) Calcium phosphate bone cements for local vancomycin delivery. Mater Sci Eng C 49:106–113. https://doi.org/10.1016/j.msec.2014.12.075

    Article  CAS  Google Scholar 

  14. Vorndran E, Geffers M, Ewald A, Lemm M, Gbureck U (2013) Ready-to-use injectable calcium phosphate bone cement paste as drug carrier. Acta Biomater 9:9558–9567. https://doi.org/10.1016/j.actbio.2013.08.009

    Article  CAS  Google Scholar 

  15. Porta GD, Campardelli R, Cricchio V, Oliva F, Maffulli N, Reverchon E (2016) Injectable PLGA/Hydroxyapatite/Chitosan microcapsules produced by supercritical emulsion extraction technology: an in vitro study on teriparatide/gentamicin controlled release. J Pharm Sci 105:2164–2172. https://doi.org/10.1016/j.xphs.2016.05.002

    Article  CAS  Google Scholar 

  16. Hamid ZAA, Tham CY, Ahmad Z (2018) Preparation and optimization of surface engineered poly(lactic acid) microspheres as a drug delivery device. J Mater Sci 53:4745–4758. https://doi.org/10.1007/s10853-017-1840-9

    Article  CAS  Google Scholar 

  17. Bharadwaz A, Jayasuriya AC, Ambalangodage C (2020) Recent trends in the application of widely used natural and synthetic polymer nanocomposites in bone tissue regeneration. Mater Sci Eng C 110:110698. https://doi.org/10.1016/j.msec.2020.110698

    Article  CAS  Google Scholar 

  18. Inzana JA, Schwarz EM, Kates SL, Awad HA (2016) Biomaterials approaches to treating implant-associated osteomyelitis. Biomaterials 81:58–71. https://doi.org/10.1016/j.biomaterials.2015.12.012

    Article  CAS  Google Scholar 

  19. Hu X, Shen H, Yang F, Liang XJ, Wang SG, Wu DC (2014) Modified composite microspheres of hydroxyapatite and poly(lactide-co-glycolide) as an injectable scaffold. Appl Surf Sci 292:764–772. https://doi.org/10.1016/j.apsusc.2013.12.045

    Article  CAS  Google Scholar 

  20. Son JS, Appleford M, Ong JL, Wenke JC, Kim JM, Choi SH, Oh DS (2011) Porous hydroxyapatite scaffold with three-dimensional localized drug delivery system using biodegradable microspheres. J Control Release 153:133–140

    Article  CAS  Google Scholar 

  21. Granado S, Cervera L, Kamen AA, Godia F (2018) Advancements in mammalian cell transient gene expression (TGE) technology for accelerated production of biologics. Crit Rev Biotechnol 38:918–940. https://doi.org/10.1080/07388551.2017.1419459

    Article  CAS  Google Scholar 

  22. Lan WT, He L, Liu YW (2018) Preparation and properties of sodium carboxymethyl cellulose/sodium alginate/chitosan composite film. Coatings 8:291. https://doi.org/10.3390/coatings8080291

    Article  CAS  Google Scholar 

  23. Qi P, Ohba S, Hara YC, Fuke M, Ogawa T, Ohta S, Ito T (2018) Fabrication of calcium phosphate-loaded carboxymethyl cellulose non-woven sheets for bone regeneration. Carbohyd Polym 189:322–330. https://doi.org/10.1016/j.carbpol.2018.02.050

    Article  CAS  Google Scholar 

  24. Chittasupho C, Thongnopkoon T, Kewsuwan P (2016) Surface modification of poly(D, L-lactic-co-glycolic acid) nanoparticles using sodium carboxymethyl cellulose as colloidal stabilizer. Curr Drug Deliv 13:95–104. https://doi.org/10.2174/1567201812666150904144241

    Article  CAS  Google Scholar 

  25. Locs J, Zalite V, Berzina-Cimdina L, Sokolova M (2013) Ammonium hydrogen carbonate provided viscous slurry foaming—A novel technology for the preparation of porous ceramics. J Eur Ceram Soc 33:3437–3443. https://doi.org/10.1016/j.jeurceramsoc.2013.06.010

    Article  CAS  Google Scholar 

  26. Irbe Z, Loca D, Vempere D, Berzina-Cimdina L (2012) Controlled release of local anesthetic from calcium phosphate bone cements. Mater Sci Eng 32:1690–1694. https://doi.org/10.1016/j.msec.2012.04.069

    Article  CAS  Google Scholar 

  27. Mao S, Xu J, Cai CF, Germershaus O, Schaper A, Kissel T (2007) Effect of WOW process parameters on morphology and burst release of FITC-dextran loaded PLGA microspheres. Int J Pharmaceut 334:137–148. https://doi.org/10.1016/j.ijpharm.2006.10.036

    Article  CAS  Google Scholar 

  28. Danhier F, Ansorena E, Silva JM, Coco R, Le Breton A, Preat V (2012) PLGA-based nanoparticles: an overview of biomedical applications. J Control Release 161:505–522. https://doi.org/10.1016/j.jconrel.2012.01.043

    Article  CAS  Google Scholar 

  29. Chaisri W, Ghassemi AH, Hennink WE, Okonogi S (2011) Enhanced gentamicin loading and release of PLGA and PLHMGA microspheres by varying the formulation parameters. Colloid Surface B 84:508–514. https://doi.org/10.1016/j.colsurfb.2011.02.006

    Article  CAS  Google Scholar 

  30. Ramazani F, Chen WL, van Nostrum CF, Storm G, Kiessling F, Lammers T, Hennink WE, Kok RJ (2016) Strategies for encapsulation of small hydrophilic and amphiphilic drugs in PLGA microspheres: state-of-the-art and challenges. Int J Pharmaceut 499:358–367. https://doi.org/10.1016/j.ijpharm.2016.01.020

    Article  CAS  Google Scholar 

  31. Sun S, Lin J, Zhang P, Fang L, Ma R, Quan ZG, Song X (2018) Geopolymer synthetized from sludge residue pretreated by the wet alkalinizing method: compressive strength and immobilization efficiency of heavy metal. Constr Build Mater 170:619–626. https://doi.org/10.1016/j.conbuildmat.2018.03.068

    Article  CAS  Google Scholar 

  32. Dhal C, Mishra R (2019) Formulation development and in vitro evaluation of gentamicin sulfate-loaded PLGA nanoparticles based film for the treatment of surgical site infection by Box-Behnken design. Drug Dev Ind Pharm 45:805–818. https://doi.org/10.1080/03639045.2019.1576719

    Article  CAS  Google Scholar 

  33. Cheng XK, He QJ, Li JQ, Huang ZL, Chi RA (2009) Control of pore size of the bubble-template porous carbonated hydroxyapatite microsphere by adjustable pressure. Cryst Growth Des 29:2770–2775. https://doi.org/10.1021/cg801421a

    Article  CAS  Google Scholar 

  34. Flores C, Degoutin S, Chai F et al (2016) Gentamicin-loaded poly(lactic-co-glycolic acid) microparticles for the prevention of maxillofacial and orthopedic implant infections. Mater Sci Eng C 64:108–116. https://doi.org/10.1016/j.msec.2016.03.064

    Article  CAS  Google Scholar 

  35. Van HN, Vu NH, Pham VH, Huan PV, Hoan BT, Nguyen DH, Manh TL (2020) A novel upconversion emission material based on Er3+–Yb3+–Mo6+ tridoped hydroxyapatite/tricalcium phosphate (HA/β-TCP). J Alloy Compd 827:154288. https://doi.org/10.1016/j.jallcom.2020.154288

    Article  CAS  Google Scholar 

  36. Zhu TT, Cui YT, Zhang MG, Zhao DY, Liu GY, Ding JX (2020) Engineered three-dimensional scaffolds for enhanced bone regeneration in osteonecrosis. Bioact Mater 5:584–601. https://doi.org/10.1016/j.bioactmat.2020.04.008

    Article  Google Scholar 

  37. Farhangdoust S, Zamanian A, Yasaei M, Khorami M (2013) The effect of processing parameters and solid concentration on the mechanical and microstructural properties of freeze-casted macroporous hydroxyapatite scaffolds. Mater Sci Eng C 33:453–460. https://doi.org/10.1016/j.msec.2012.09.013

    Article  CAS  Google Scholar 

  38. Cui LG, Zhang J, Zou J et al (2020) Electroactive composite scaffold with locally expressed osteoinductive factor for synergistic bone repair upon electrical stimulation. Biomaterials 230:119617. https://doi.org/10.1016/j.biomaterials.2019.119617

    Article  CAS  Google Scholar 

  39. Lai YX, Cao HJ, Wang XL et al (2018) Porous composite scaffold incorporating osteogenic phytomolecule icariin for promoting skeletal regeneration in challenging osteonecrotic bone in rabbits. Biomaterials 153:1–13. https://doi.org/10.1016/j.biomaterials.2017.10.025

    Article  CAS  Google Scholar 

  40. Wu CT, Ramaswamy Y, Zreiqat H (2010) Porous diopside (CaMgSi2O6) scaffold: a promising bioactive material for bone tissue engineering. Acta Biomater 6:2237–2245. https://doi.org/10.1016/j.actbio.2009.12.022

    Article  CAS  Google Scholar 

  41. Zhao XY, Han Y, Zhu TT et al (2019) Electrospun polylactide-nano-hydroxyapatite-vancomycin composite scaffolds for advanced osteomyelitis therapy. J Biomed Nanotechnol 15:1213–1222. https://doi.org/10.1166/jbn.2019.2773

    Article  CAS  Google Scholar 

  42. Li SQ, Dong SJ, Xu WG, Tu SC, Yan LS, Zhao CW, Ding JX, Chen XS (2018) Antibacterial Hydrogels. Adv Sci 5:1700527. https://doi.org/10.1002/advs.201700527

    Article  CAS  Google Scholar 

  43. Dulon D, Aurousseau C, Erre JP, Aran JM (1988) Relationship between the nephrotoxicity and ototoxicity induced by gentamicin in the guinea pig. Acta Oto-Laryngol 106:219–225. https://doi.org/10.3109/00016488809106429

    Article  CAS  Google Scholar 

  44. Posadowska U, Brzychczy-Włoch M, Drożdż A, Krok-Borkowicz M, Włodarczyk-Biegun M, Dobrzyński P, Chrzanowski W, Pamula E (2016) Injectable hybrid delivery system composed of gellan gum, nanoparticles and gentamicin for the localized treatment of bone infections. Expert Opin Drug Del 13:613–620. https://doi.org/10.1517/17425247.2016.1146673

    Article  CAS  Google Scholar 

  45. Wang GH, Liu SJ, Ueng SWN, Chan EC (2004) The release of cefazolin and gentamicin from biodegradable PLA/PGA beads. Int J Pharmaceut 273:203–212. https://doi.org/10.1016/j.ijpharm.2004.01.010

    Article  CAS  Google Scholar 

  46. Fredenberg S, Wahlgren M, Reslow M et al (2011) The mechanisms of drug release in poly(lactic-co-glycolic acid)-based drug delivery systems—A review. Int J Pharmaceut 415:34–52. https://doi.org/10.1016/j.ijpharm.2011.05.049

    Article  CAS  Google Scholar 

  47. Gasmi H, Siepmann F, Hamoudi MC, Axelsson A (2016) Towards a better understanding of the different release phases from PLGA microparticles: dexamethasone-loaded systems. Int J Pharmaceut 514:189–199. https://doi.org/10.1016/j.ijpharm.2016.08.032

    Article  CAS  Google Scholar 

  48. Roth KE, Maier GS, Schmidtmann I, Eigner U, Huebner WD, Peters F, Drees P, Maus U (2019) Release of antibiotics out of a moldable collagen-beta-tricalciumphosphate-composite compared to two calcium phosphate granules. Materials 12:4056. https://doi.org/10.3390/ma12244056

    Article  CAS  Google Scholar 

  49. Memar MY, Adibkia K, Farajnia S, Kafil HS, Dizaj SM, Ghotaslou R (2019) Biocompatibility, cytotoxicity and antimicrobial effects of gentamicin-loaded CaCO3 as a drug delivery to osteomyelitis. J Drug Deliv Sci Tec 54:101307. https://doi.org/10.1016/j.jddst.2019.101307

    Article  CAS  Google Scholar 

  50. Choi CK, Kim H, Kwon H, Annable MD (2017) Effect of increased groundwater viscosity on the remedial performance of surfactant-enhanced air sparging. J Contam Hydrol 77:69–75. https://doi.org/10.1016/j.msec.2017.03.215

    Article  CAS  Google Scholar 

  51. Zhao D, Zhu TT, Li J, Cui LG, Zhang ZY, Zhuang XL, Ding JX (2021) Poly(lactic-co-glycolic acid)-based composite bone-substitute materials. Bioact Mater 6:346–360. https://doi.org/10.1016/j.bioactmat.2020.08.016

    Article  CAS  Google Scholar 

  52. Szczeblinska J, Fijalkowski K, Kohn J, El Fray M (2017) Antibiotic loaded microspheres as antimicrobial delivery systems for medical applications. Mater Sci Eng C 77:69–75. https://doi.org/10.1016/j.msec.2017.03.215

    Article  CAS  Google Scholar 

  53. Rostami F, Tamjid E, Behmanesh M (2020) Drug-eluting PCL/graphene oxide nanocomposite scaffolds for enhanced osteogenic differentiation of mesenchymal stem cells. Mater Sci Eng C 115:111102. https://doi.org/10.1016/j.msec.2020.111102

    Article  CAS  Google Scholar 

  54. Zennifer A, Senthilvelan P, Sethuraman S, Sundaramurthi D (2021) Key advances of carboxymethyl cellulose in tissue engineering and 3D bioprinting applications. Carbohyd Polym 256:117561. https://doi.org/10.1016/j.carbpol.2020.117561

    Article  CAS  Google Scholar 

  55. Chahal S, Hussain FSJ, Kumar A, Rasad MSBA, Yusoff MM (2016) Fabrication, characterization and in vitro biocompatibility of electrospun hydroxyethyl cellulose/poly (vinyl) alcohol nanofibrous composite biomaterial for bone tissue engineering. Chem Eng Sci 144:17–29. https://doi.org/10.1016/j.ces.2015.12.030

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the China National Natural Science Foundation (No. 51878410), the China National Natural Science Foundation (No. 11672090) and the Shenzhen Science and Technology Planning Project (No. JCYJ20180507182310677).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rui Ma.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Handling Editor: Lisa White.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 1826 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cao, X., Dai, L., Sun, S. et al. Preparation and performance of porous hydroxyapatite/poly(lactic-co-glycolic acid) drug-loaded microsphere scaffolds for gentamicin sulfate delivery. J Mater Sci 56, 15278–15298 (2021). https://doi.org/10.1007/s10853-021-06183-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10853-021-06183-8

Navigation