AAPS PharmSciTech

, Volume 18, Issue 2, pp 529–538 | Cite as

Preparation and Evaluations of Mangiferin-Loaded PLGA Scaffolds for Alveolar Bone Repair Treatment Under the Diabetic Condition

Research Article
  • 335 Downloads

Abstract

The aim of the present study was to prepare and evaluate a sustained-release mangiferin scaffold for improving alveolar bone defect repair in diabetes. Mangiferin-loaded poly(D,L-lactide-co-glycolide) (PLGA) scaffolds were prepared using a freeze-drying technique with ice particles as the porogen material. The produced scaffolds were examined using a scanning electron microscope (SEM). Drug content and drug release were detected using a spectrophotometer. Degradation behaviors were monitored as a measure of weight loss and examined using SEM. Then, the scaffolds were incubated with rat bone marrow stromal cells under the diabetic condition in vitro, and cell viability was assessed using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Afterward, the scaffolds were implanted into alveolar bone defects of diabetic rats, and bone repair was examined using hematoxylin and eosin staining. The fabricated scaffolds showed porous structures, with average pore size range from 111.35 to 169.45 μm. A higher PLGA concentration led to decreased average pore size. A lower PLGA concentration or a higher mangiferin concentration resulted in increased drug content. The prepared scaffolds released mangiferin in a sustained manner with relatively low initial burst during 10 weeks. Their degradation ratios gradually increased as degradation proceeded. The mangiferin-loaded scaffolds attenuated cell viability decrease under the diabetic condition in vitro. Moreover, they increased histological scorings of bone regeneration and improved delayed alveolar bone defect healing in diabetic rats. These results suggest that the produced mangiferin-loaded scaffolds may provide a potential approach in the treatment of impaired alveolar bone healing in diabetes.

KEY WORDS

alveolar bone repair diabetes mangiferin scaffold 

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81200794), Guangxi Natural Science Foundation (No. 2015GXNSFBA139140), Guangxi Scientific and Technologic Research Project of Colleges and Universities (No. KY2015YB060), and Youth Science Foundation of Guangxi Medical University (No. GXMUYSF2014017).

References

  1. 1.
    Cramer C, Freisinger E, Jones R, Slakey D, Dupin C, Newsome E, et al. Persistent high glucose concentrations alter the regenerative potential of mesenchymal stem cells. Stem Cells Dev. 2010;19:1875–84.CrossRefPubMedGoogle Scholar
  2. 2.
    Jiao H, Xiao E, Graves D. Diabetes and its effect on bone and fracture healing. Curr Osteoporos Rep. 2015;13:327–35.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    He H, Liu R, Desta T, Leone C, Gerstenfeld L, Graves D. Diabetes causes decreased osteoclastogenesis, reduced bone formation, and enhanced apoptosis of osteoblastic cells in bacteria stimulated bone loss. Endocrinology. 2004;145:447–52.CrossRefPubMedGoogle Scholar
  4. 4.
    Wang Q, Li H, Xiao Y, Li S, Li B, Zhao X, et al. Locally controlled delivery of TNFα antibody from a novel glucose-sensitive scaffold enhances alveolar bone healing in diabetic conditions. J Control Release. 2015;206:232–42.CrossRefPubMedGoogle Scholar
  5. 5.
    Rivera D, Hernández I, Merino N, Luque Y, Álvarez A, Martín Y, et al. Mangifera indica L. extract (Vimang) and mangiferin reduce the airway inflammation and Th2 cytokines in murine model of allergic asthma. J Pharm Pharmacol. 2011;63:1336–45.CrossRefPubMedGoogle Scholar
  6. 6.
    Márquez L, García-Bueno B, Madrigal J, Leza J. Mangiferin decreases inflammation and oxidative damage in rat brain after stress. Eur J Nutr. 2012;51:729–39.CrossRefPubMedGoogle Scholar
  7. 7.
    Pal P, Sinha K, Sil P. Mangiferin attenuates diabetic nephropathy by inhibiting oxidative stress mediated signaling cascade, TNFα related and mitochondrial dependent apoptotic pathways in streptozotocin-induced diabetic rats. PLoS One. 2014;9:e107220.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kokotkiewicz A, Luczkiewicz M, Pawlowska J, Luczkiewicz P, Sowinski P, Witkowski J, et al. Isolation of xanthone and benzophenone derivatives from Cyclopia genistoides (L.) Vent. (honeybush) and their pro-apoptotic activity on synoviocytes from patients with rheumatoid arthritis. Fitoterapia. 2013;90:199–208.CrossRefPubMedGoogle Scholar
  9. 9.
    Luo Y, Fu C, Wang Z, Zhang Z, Wang H, Liu Y. Mangiferin attenuates contusive spinal cord injury in rats through the regulation of oxidative stress, inflammation and the Bcl-2 and Bax pathway. Mol Med Rep. 2015;12:7132–8.PubMedGoogle Scholar
  10. 10.
    Huh J, Koh P, Seo B, Park Y, Baek Y, Lee J, et al. Mangiferin reduces the inhibition of chondrogenic differentiation by IL-1β in mesenchymal stem cells from subchondral bone and targets multiple aspects of the Smad and SOX9 pathways. Int J Mol Sci. 2014;15:16025–42.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Carvalho R, Pellizzon C, Justulin LJ, Felisbino S, Vilegas W, Bruni F, et al. Effect of mangiferin on the development of periodontal disease: involvement of lipoxin A4, anti-chemotaxic action in leukocyte rolling. Chem Biol Interact. 2009;179:344–50.CrossRefPubMedGoogle Scholar
  12. 12.
    Jagetia G, Baliga M. Radioprotection by mangiferin in DBAxC57BL mice: a preliminary study. Phytomedicine. 2005;12:209–15.CrossRefPubMedGoogle Scholar
  13. 13.
    Hou S, Wang F, Li Y, Li Y, Wang M, Sun D, et al. Pharmacokinetic study of mangiferin in human plasma after oral administration. Food Chem. 2012;132:289–94.CrossRefPubMedGoogle Scholar
  14. 14.
    Xiao W, Hou J, Ma J, Yu B, Ren J, Jin W, et al. Mangiferin loaded magnetic PCEC microspheres: preparation, characterization and antitumor activity studies in vitro. Arch Pharm Res. 2014.Google Scholar
  15. 15.
    Chang N, Lam C, Lin C, Chen W, Li C, Lin Y, et al. Transplantation of autologous endothelial progenitor cells in porous PLGA scaffolds create a microenvironment for the regeneration of hyaline cartilage in rabbits. Osteoarthr Cartil. 2013;21:1613–22.CrossRefPubMedGoogle Scholar
  16. 16.
    Yoon S, Park K, Kim M, Rhee J, Khang G, Lee H. Repair of diaphyseal bone defects with calcitriol-loaded PLGA scaffolds and marrow stromal cells. Tissue Eng. 2007;13:1125–33.CrossRefPubMedGoogle Scholar
  17. 17.
    Lee H, Seo S, Chang H, Bang J, Joung Y, Son T, et al. Fabrication and characteristics of anti-inflammatory magnesium hydroxide incorporated PLGA scaffolds formed with various porogen materials. Macromol Res. 2014;22:210–8.CrossRefGoogle Scholar
  18. 18.
    Jeon O, Song S, Kang S, Putnam A, Kim B. Enhancement of ectopic bone formation by bone morphogenetic protein-2 released from a heparin-conjugated poly(L-lactic-co-glycolic acid) scaffold. Biomaterials. 2007;28:2763–71.CrossRefPubMedGoogle Scholar
  19. 19.
    Song J, Xie J, Li C, Lu J, Meng Q, Yang Z, et al. Near infrared spectroscopic (NIRS) analysis of drug-loading rate and particle size of risperidone microspheres by improved chemometric model. Int J Pharm. 2014;472:296–303.CrossRefPubMedGoogle Scholar
  20. 20.
    Hedberg E, Shih C, Lemoine J, Timmer M, Liebschner M, Jansen J, et al. In vitro degradation of porous poly(propylene fumarate)/poly(DL-lactic-co-glycolic acid) composite scaffolds. Biomaterials. 2005;26:3215–25.CrossRefPubMedGoogle Scholar
  21. 21.
    Souza J, Carvalho J, Trevisan M, Paula R, Ricardo N, Feitosa J. Chitosan-coated pectin beads: characterization and in vitro release of mangiferin. food hydrocoll. 2009;23:2278–86.CrossRefGoogle Scholar
  22. 22.
    Kretlow J, Klouda L, Mikos A. Injectable matrices and scaffolds for drug delivery in tissue engineering. Adv Drug Deliv Rev. 2007;59:263–73.CrossRefPubMedGoogle Scholar
  23. 23.
    Sharma A, Bharti S, Kumar R, Krishnamurthy B, Bhatia J, Kumari S, et al. Syzygium cumini ameliorates insulin resistance and β-cell dysfunction via modulation of PPAR, dyslipidemia, oxidative stress, and TNF-α in type 2 diabetic rats. J Pharmacol Sci. 2012;119:205–13.CrossRefPubMedGoogle Scholar
  24. 24.
    Ravi N, Gupta G, Milbrandt T, Puleo D. Porous PLGA scaffolds for controlled release of naked and polyethyleneimine-complexed DNA. Biomed Mater. 2012;7:055007.CrossRefPubMedGoogle Scholar
  25. 25.
    Liu M, Dai L, Shi H, Xiong S, Zhou C. In vitro evaluation of alginate/halloysite nanotube composite scaffolds for tissue engineering. Mater Sci Eng C Mater Biol Appl. 2015;49:700–12.CrossRefPubMedGoogle Scholar
  26. 26.
    Hu Y, Ma S, Yang Z, Zhou W, Du Z, Huang J, et al. Facile fabrication of poly(L-lactic acid) microsphere-incorporated calcium alginate/hydroxyapatite porous scaffolds based on Pickering emulsion templates. Colloids Surf B: Biointerfaces. 2016;140:382–91.CrossRefPubMedGoogle Scholar
  27. 27.
    Kim K, Dean D, Wallace J, Breithaupt R, Mikos A, Fisher J. The influence of stereolithographic scaffold architecture and composition on osteogenic signal expression with rat bone marrow stromal cells. Biomaterials. 2011;32:3750–63.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Watanabe K, Petro B, Shlimon A, Unterman T. Effect of periodontitis on insulin resistance and the onset of type 2 diabetes mellitus in Zucker diabetic fatty rats. J Periodontol. 2008;79:1208–16.CrossRefPubMedGoogle Scholar
  29. 29.
    Li H, Wang Q, Xiao Y, Bao C, Li W. 25-Hydroxyvitamin D(3)-loaded PLA microspheres: in vitro characterization and application in diabetic periodontitis models. AAPS PharmSciTech. 2013;14:880–9.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Lane J, Sandhu H. Current approaches to experimental bone grafting. Orthop Clin North Am. 1987;18:213–25.PubMedGoogle Scholar
  31. 31.
    Zhu X, Cheng Y, Du L, Li Y, Zhang F, Guo H, et al. Mangiferin attenuates renal fibrosis through down-regulation of osteopontin in diabetic rats. Phytother Res. 2015;29:295–302.CrossRefPubMedGoogle Scholar
  32. 32.
    Mandal B, Kundu S. Calcium alginate beads embedded in silk fibroin as 3D dual drug releasing scaffolds. Biomaterials. 2009;30:5170–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Wang J, Yang W, Xie H, Song Y, Li Y, Wang L. Ischemic stroke and repair: current trends in research and tissue engineering treatments. Regen Med Res. 2014;2:3.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Wang Y, Liu X, Zhao J, Kong X, Shi R, Zhao X, et al. Degradable PLGA scaffolds with basic fibroblast growth factor: experimental studies in myocardial revascularization. Tex Heart Inst J. 2009;36:89–97.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Liu B, Cai S, Ma K, Xu Z, Dai X, Yang L, et al. Fabrication of a PLGA-collagen peripheral nerve scaffold and investigation of its sustained release property in vitro. J Mater Sci Mater Med. 2008;19:1127–32.CrossRefPubMedGoogle Scholar
  36. 36.
    Oh S, Kang S, Lee J. Degradation behavior of hydrophilized PLGA scaffolds prepared by melt-molding particulate-leaching method: comparison with control hydrophobic one. J Mater Sci Mater Med. 2006;17:131–7.CrossRefPubMedGoogle Scholar
  37. 37.
    Khaled K, Sarhan H, Ibrahim M, Ali A, Naguib Y. Prednisolone-loaded PLGA microspheres. In vitro characterization and in vivo application in adjuvant-induced arthritis in mice. AAPS PharmSciTech. 2010;11:859–69.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Lee D, Kwon T, Kim K, Kwon S, Cho D, Jang S, et al. Anti-inflammatory drug releasing absorbable surgical sutures using poly(lactic-co-glycolic acid) particle carriers. Polym Bull. 2014;71:1933–46.CrossRefGoogle Scholar
  39. 39.
    Brochhausen C, Zehbe R, Watzer B, Halstenberg S, Gabler F, Schubert H, et al. Immobilization and controlled release of prostaglandin E2 from poly-L-lactide-co-glycolide microspheres. J Biomed Mater Res A. 2009;91:454–62.CrossRefPubMedGoogle Scholar
  40. 40.
    Brownfield L, Weltman R. Ridge preservation with or without an osteoinductive allograft: a clinical, radiographic, micro-computed tomography, and histologic study evaluating dimensional changes and new bone formation of the alveolar ridge. J Periodontol. 2012;85:581–9.CrossRefGoogle Scholar
  41. 41.
    Jonnalagadda J, Rivero I, Dertien J. In vitro chondrocyte behavior on porous biodegradable poly(e-caprolactone)/polyglycolic acid scaffolds for articular chondrocyte adhesion and proliferation. J Biomater Sci Polym Ed. 2015;26:401–19.CrossRefPubMedGoogle Scholar
  42. 42.
    Song J, Li J, Hou F, Wang X, Liu B. Mangiferin inhibits endoplasmic reticulum stress-associated thioredoxin-interacting protein/NLRP3 inflammasome activation with regulation of AMPK in endothelial cells. Metabolism. 2015;64:428–37.CrossRefPubMedGoogle Scholar
  43. 43.
    Lee C, Lee Y. Preparation of porous biodegradable poly(lactide-co-glycolide)/hyaluronic acid blend scaffolds: characterization, in vitro cells culture and degradation behaviors. J Mater Sci Mater Med. 2006;17:1411–20.CrossRefPubMedGoogle Scholar
  44. 44.
    Chang P, Chung M, Wang Y, Chien L, Lim J, Liang K, et al. Patterns of diabetic periodontal wound repair: a study using micro-computed tomography and immunohistochemistry. J Periodontol. 2012;83:644–52.CrossRefPubMedGoogle Scholar
  45. 45.
    Graves D, Alblowi J, Paglia D, O’Connor J, Lin S. Impact of diabetes on fracture healing. J Exp Clin Med. 2011;3:3–8.CrossRefGoogle Scholar
  46. 46.
    Stolzing A, Sellers D, Llewelyn O, Scutt A. Diabetes induced changes in rat mesenchymal stem cells. Cells Tissues Organs. 2010;191:453–65.CrossRefPubMedGoogle Scholar
  47. 47.
    Das A, Fishero B, Christophel J, Li C, Kohli N, Lin Y, et al. Poly(lactic-co-glycolide) polymer constructs cross-linked with human BMP-6 and VEGF protein significantly enhance rat mandible defect repair. Cell Tissue Res. 2015.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2016

Authors and Affiliations

  1. 1.Department of Prosthodontics, the Affiliated Hospital of StomatologyGuangxi Medical UniversityNanningPeople’s Republic of China
  2. 2.State Key Laboratory of Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduPeople’s Republic of China

Personalised recommendations