Tissue Scaffolds As a Local Drug Delivery System for Bone Regeneration

  • Elif Sarigol-Calamak
  • Canan HascicekEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1078)


Healing fractures resulting from bone disorders such as osteoporosis, osteoarthritis, osteomyelitis, and osteosarcoma remain a significant clinical challenge. In this chapter, we focus on scaffold based local drug delivery applications for promoting bone regeneration. For this purpose, we first review bone disorders, which require drug treatment and current fabrication techniques for bone tissue scaffold as a drug carrier. Next, we address the role of antimicrobial agents, anti-inflammatory drugs, anti-cancer drugs and bisphosphonates in promoting vascularized bone regeneration and discuss various local therapeutic delivery strategies for controlled and sustained drug delivery. Specifically, this review addresses the concept of drug loaded scaffold design and local drug release effects on bone regeneration. We conclude this review with a discussion of local drug delivery approaches to bone regeneration and discuss why it has the potential to be more efficient than traditional bone treatment methods.


Bone disorders Local drug delivery Bone regeneration Tissue scaffold Pharmacological treatment Scaffold fabrication 


  1. 1.
    Andronescu E, Ficai A, Albu MG, Mitran V, Sonmez M, Ficai D, Ion R, Cimpean A (2013) Collagen-hydroxyapatite/cisplatin drug delivery systems for locoregional treatment of bone cancer. Technol Cancer Res Treat 12(4):275–284PubMedCrossRefGoogle Scholar
  2. 2.
    Anselme K (2000) Osteoblast adhesion on biomaterials. Biomaterials 21(7):667–681PubMedCrossRefGoogle Scholar
  3. 3.
    Aydemir Sezer U, Arslantunali D, Aksoy EA, Hasirci V, Hasirci N (2014) Poly (ε-caprolactone) composite scaffolds loaded with gentamicin-containing β-tricalcium phosphate/gelatin microspheres for bone tissue engineering applications. J Appl Polym Sci 131(8)Google Scholar
  4. 4.
    Babaie E, Lin B, Bhaduri SB (2017) A new method to produce macroporous Mg-phosphate bone growth substitutes. Mater Sci Eng C 75:602–609CrossRefGoogle Scholar
  5. 5.
    Baron R, Hesse E (2012) Update on bone anabolics in osteoporosis treatment: rationale, current status, and perspectives. J Clin Endocrinol Metabol 97(2):311–325CrossRefGoogle Scholar
  6. 6.
    Barrère F, van Blitterswijk CA, de Groot K (2006) Bone regeneration: molecular and cellular interactions with calcium phosphate ceramics. Int J Nanomedicine 1(3):317–332PubMedPubMedCentralGoogle Scholar
  7. 7.
    Bennet D, Marimuthu M, Kim S, An J (2012) Dual drug-loaded nanoparticles on self-integrated scaffold for controlled delivery. Int J Nanomedicine 7:3399PubMedPubMedCentralGoogle Scholar
  8. 8.
    Bhattacharyya S, Nair LS, Singh A, Krogman NR, Greish YE, Brown PW, Allcock HR, Laurencin CT (2006) Electrospinning of poly [bis (ethyl alanato) phosphazene] nanofibers. J Biomed Nanotechnol 2(1):36–45CrossRefGoogle Scholar
  9. 9.
    Bhattacharyya S, Kumbar SG, Khan YM, Nair LS, Singh A, Krogman NR, Brown PW, Allcock HR, Laurencin CT (2009) Biodegradable polyphosphazene-nanohydroxyapatite composite nanofibers: scaffolds for bone tissue engineering. J Biomed Nanotechnol 5(1):69–75PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Bhattarai N, Gunn J, Zhang M (2010) Chitosan-based hydrogels for controlled, localized drug delivery. Adv Drug Deliv Rev 62(1):83–99PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Bignon A, Chouteau J, Chevalier J, Fantozzi G, Carret J-P, Chavassieux P, Boivin G, Melin M, Hartmann D (2003) Effect of micro-and macroporosity of bone substitutes on their mechanical properties and cellular response. J Mater Sci Mater Med 14(12):1089–1097PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Bijlsma JW, Berenbaum F, Lafeber FP (2011) Osteoarthritis: an update with relevance for clinical practice. Lancet 377(9783):2115–2126CrossRefGoogle Scholar
  13. 13.
    Çalamak S, Erdoğdu C, Özalp M, Ulubayram K (2014) Silk fibroin based antibacterial bionanotextiles as wound dressing materials. Mater Sci Eng C 43:11–20CrossRefGoogle Scholar
  14. 14.
    Calamak S, Aksoy EA, Erdogdu C, Sagıroglu M, Ulubayram K (2015) Silver nanoparticle containing silk fibroin bionanotextiles. J Nanopart Res 17(2):87CrossRefGoogle Scholar
  15. 15.
    Calamak S, Aksoy EA, Ertas N, Erdogdu C, Sagıroglu M, Ulubayram M (2015) Ag/silk fibroin nanofibers: effect of fibroin morphology on Ag+ release and antibacterial activity. Eur Polym J 67:99–112CrossRefGoogle Scholar
  16. 16.
    Calamak S, Shahbazi R, Eroglu I, Gultekinoglu M, Ulubayram K (2017) An overview of nanofiber-based antibacterial drug design. Expert Opin Drug Discovery 12:391–406CrossRefGoogle Scholar
  17. 17.
    Cancedda R (2009) Cartilage and bone extracellular matrix. Curr Pharm Des 15(12):1334–1348PubMedCrossRefGoogle Scholar
  18. 18.
    Chapurlat R, Delmas P (2004) New treatments in osteoporosis. Revue Med Interne 25:S573–S579CrossRefGoogle Scholar
  19. 19.
    Chen Y, Kawazoe N, Chen G (2017) Preparation of dexamethasone-loaded biphasic calcium phosphate nanoparticles/collagen porous composite scaffolds for bone tissue engineering. Acta Biomater 67:341–353PubMedCrossRefGoogle Scholar
  20. 20.
    Cheng T, Qu H, Zhang G, Zhang X (2017) Osteogenic and antibacterial properties of vancomycin-laden mesoporous bioglass/PLGA composite scaffolds for bone regeneration in infected bone defects. Artif Cells Nanomed Biotechnol:1–13Google Scholar
  21. 21.
    Cicuéndez M, Doadrio JC, Hernández A, Portolés MT, Izquierdo-Barba I, Vallet-Regí M (2018) Multifunctional pH sensitive 3D scaffolds for treatment and prevention of bone infection. Acta Biomater 65:450–461PubMedCrossRefGoogle Scholar
  22. 22.
    Cooke MN, Fisher JP, Dean D, Rimnac C, Mikos AG (2003) Use of stereolithography to manufacture critical-sized 3D biodegradable scaffolds for bone ingrowth. J Biomed Mater Res B Appl Biomater 64(2):65–69PubMedCrossRefGoogle Scholar
  23. 23.
    Cutolo M, Berenbaum F, Hochberg M, Punzi L, Reginster J-Y (2015) Commentary on recent therapeutic guidelines for osteoarthritis. Semin Arthritis Rheum 44(6):611–617 ElsevierPubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Decambron A, Manassero M, Bensidhoum M, Lecuelle B, Logeart-Avramoglou D, Petite H, Viateau V (2017) A comparative study of tissue-engineered constructs from Acropora and Porites coral in a large animal bone defect model. Bone Joint Res 6(4):208–215PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Denry I, Holloway JA (2014) Low temperature sintering of fluorapatite glass-ceramics. Dent Mater 30(2):112–121PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Denry I, Goudouri OM, Harless J, Holloway JA (2018) Rapid vacuum sintering: a novel technique for fabricating fluorapatite ceramic scaffolds for bone tissue engineering. J Biomed Mater Res B Appl Biomater 106(1):291–299PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Devin JE, Attawia MA, Laurencin CT (1996) Three-dimensional degradable porous polymer-ceramic matrices for use in bone repair. J Biomater Sci Polym Ed 7(8):661–669PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Downey PA, Siegel MI (2006) Bone biology and the clinical implications for osteoporosis. Phys Ther 86(1):77–91PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Durucan C, Brown PW (2000) Calcium-deficient hydroxyapatite-PLGA composites: mechanical and microstructural investigation. J Biomed Mater Res A 51(4):726–734CrossRefGoogle Scholar
  30. 30.
    Ezra A, Golomb G (2000) Administration routes and delivery systems of bisphosphonates for the treatment of bone resorption. Adv Drug Deliv Rev 42(3):175–195PubMedCrossRefGoogle Scholar
  31. 31.
    Farooq A, Yar M, Khan AS, Shahzadi L, Siddiqi SA, Mahmood N, Rauf A, Manzoor F, Chaudhry AA, ur Rehman I (2015) Synthesis of piroxicam loaded novel electrospun biodegradable nanocomposite scaffolds for periodontal regeneration. Mater Sci Eng C 56:104–113CrossRefGoogle Scholar
  32. 32.
    Feng X, McDonald JM (2011) Disorders of bone remodeling. Annu Rev Pathol Mech Dis 6:121–145CrossRefGoogle Scholar
  33. 33.
    Fischer P, Romano V, Weber H-P, Karapatis N, Boillat E, Glardon R (2003) Sintering of commercially pure titanium powder with a Nd: YAG laser source. Acta Mater 51(6):1651–1662CrossRefGoogle Scholar
  34. 34.
    Florencio-Silva R, Sasso GR d S, Sasso-Cerri E, Simões MJ, Cerri PS (2015) Biology of bone tissue: structure, function, and factors that influence bone cells. Biomed Res Int 2015:421746PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Fu Q, Saiz E, Rahaman MN, Tomsia AP (2011) Bioactive glass scaffolds for bone tissue engineering: state of the art and future perspectives. Mater Sci Eng C 31(7):1245–1256CrossRefGoogle Scholar
  36. 36.
    Gitelis S, Brebach GT (2002) The treatment of chronic osteomyelitis with a biodegradable antibiotic-impregnated implant. J Orthop Surg 10(1):53–60CrossRefGoogle Scholar
  37. 37.
    Glyn-Jones S, Palmer A, Price A, Vincent T, Weinans H, Carr AJ (2015) Osteoarthritis. Lancet 386(9991):376–387CrossRefGoogle Scholar
  38. 38.
    Govender T, Stolnik S, Garnett MC, Illum L, Davis SS (1999) PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug. J Control Release 57(2):171–185PubMedCrossRefGoogle Scholar
  39. 39.
    Gu W, Wu C, Chen J, Xiao Y (2013) Nanotechnology in the targeted drug delivery for bone diseases and bone regeneration. Int J Nanomedicine 8:2305PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Guo J, Zhang Q, Li J, Liu Y, Hou Z, Chen W, Jin L, Tian Y, Ju L, Liu B (2017) Local application of an ibandronate/collagen sponge improves femoral fracture healing in ovariectomized rats. PLoS One 12(11):e0187683PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Hamadouche M, Sedel L (2000) Ceramics in orthopaedics. Bone Joint J 82(8):1095–1099CrossRefGoogle Scholar
  42. 42.
    Hatzenbuehler J, Pulling TJ (2011) Diagnosis and management of osteomyelitis. Am Fam Physician 84(9):1027–1033PubMedPubMedCentralGoogle Scholar
  43. 43.
    Heino TJ, Hentunen TA, Väänänen HK (2004) Conditioned medium from osteocytes stimulates the proliferation of bone marrow mesenchymal stem cells and their differentiation into osteoblasts. Exp Cell Res 294(2):458–468PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Henderson PW, Singh SP, Krijgh DD, Yamamoto M, Rafii DC, Sung JJ, Rafii S, Rabbany SY, Spector JA (2011) Stromal-derived factor-1 delivered via hydrogel drug-delivery vehicle accelerates wound healing in vivo. Wound Repair Regen 19(3):420–425PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Hess U, Shahabi S, Treccani L, Streckbein P, Heiss C, Rezwan K (2017) Co-delivery of cisplatin and doxorubicin from calcium phosphate beads/matrix scaffolds for osteosarcoma therapy. Mater Sci Eng C 77:427–435CrossRefGoogle Scholar
  46. 46.
    Hirabayashi H, Fujisaki J (2003) Bone-specific drug delivery systems. Clin Pharmacokinet 42(15):1319–1330PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Holzwarth JM, Ma PX (2011) Biomimetic nanofibrous scaffolds for bone tissue engineering. Biomaterials 32(36):9622–9629PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Iacono MV (2007) Osteoporosis: a national public health priority. J Perianesth Nurs 22(3):175–183PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Iannazzo D, Pistone A, Espro C, Galvagno S (2015) Drug delivery strategies for bone tissue regeneration. In: Panseri S, Taraballi F, Cunha C (eds) Biomimetic approaches for tissue healing. OMICS International, Foster City, pp 1–39Google Scholar
  50. 50.
    Inzana JA, Trombetta RP, Schwarz EM, Kates SL, Awad HA (2015) 3D printed bioceramics for dual antibiotic delivery to treat implant-associated bone infection. Eur Cell Mater 30:232–247PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Iseme RA, Mcevoy M, Kelly B, Agnew L, Walker FR, Attia J (2017) Is osteoporosis an autoimmune mediated disorder? Bone Rep 7:121–131PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Jiang S, Zhang Y, Shu Y, Wu Z, Cao W, Huang W (2017) Amino-functionalized mesoporous bioactive glass for drug delivery. Biomed Mater 12(2):025017PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Jo YS, Rizzi SC, Ehrbar M, Weber FE, Hubbell JA, Lutolf MP (2010) Biomimetic PEG hydrogels crosslinked with minimal plasmin-sensitive tri-amino acid peptides. J Biomed Mater Res A 93(3):870–877PubMedPubMedCentralGoogle Scholar
  54. 54.
    Kim H-W, Knowles JC, Kim H-E (2004) Hydroxyapatite/poly (ε-caprolactone) composite coatings on hydroxyapatite porous bone scaffold for drug delivery. Biomaterials 25(7–8):1279–1287PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Kim HW, Knowles JC, Kim HE (2004) Development of hydroxyapatite bone scaffold for controlled drug release via poly (ε-caprolactone) and hydroxyapatite hybrid coatings. J Biomed Mater Res B Appl Biomater 70(2):240–249PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Kim H-W, Knowles JC, Kim H-E (2005) Hydroxyapatite porous scaffold engineered with biological polymer hybrid coating for antibiotic Vancomycin release. J Mater Sci Mater Med 16(3):189–195PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Kim K, Yeatts A, Dean D, Fisher JP (2010) Stereolithographic bone scaffold design parameters: osteogenic differentiation and signal expression. Tissue Eng Part B Rev 16(5):523–539PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Kini U, Nandeesh B (2012) Physiology of bone formation, remodeling, and metabolism. In: Radionuclide and hybrid bone imaging. Springer, Berlin, pp 29–57CrossRefGoogle Scholar
  59. 59.
    Kokubo T, Ito S, Huang Z, Hayashi T, Sakka S, Kitsugi T, Yamamuro T (1990) Ca, P-rich layer formed on high-strength bioactive glass-ceramic A-W. J Biomed Mater Res A 24(3):331–343CrossRefGoogle Scholar
  60. 60.
    Kothapalli C, Wei M, Vasiliev A, Shaw M (2004) Influence of temperature and concentration on the sintering behavior and mechanical properties of hydroxyapatite. Acta Mater 52(19):5655–5663CrossRefGoogle Scholar
  61. 61.
    Kundu B, Soundrapandian C, Nandi SK, Mukherjee P, Dandapat N, Roy S, Datta BK, Mandal TK, Basu D, Bhattacharya RN (2010) Development of new localized drug delivery system based on ceftriaxone-sulbactam composite drug impregnated porous hydroxyapatite: a systematic approach for in vitro and in vivo animal trial. Pharm Res 27(8):1659–1676PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Langton C, Whitehead M, Langton D, Langley G (1997) Development of a cancellous bone structural model by stereolithography for ultrasound characterisation of the calcaneus. Med Eng Phys 19(7):599–604PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Lasprilla AJ, Martinez GA, Lunelli BH, Jardini AL, Maciel Filho R (2012) Poly-lactic acid synthesis for application in biomedical devices—a review. Biotechnol Adv 30(1):321–328PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Lew DP, Waldvogel FA (2004) Osteomyelitis. Lancet 364(9431):369–379PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Liao S, Cui F, Zhang W, Feng Q (2004) Hierarchically biomimetic bone scaffold materials: nano-HA/collagen/PLA composite. J Biomed Mater Res B Appl Biomater 69(2):158–165PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Lienemann PS, Karlsson M, Sala A, Wischhusen HM, Weber FE, Zimmermann R, Weber W, Lutolf MP, Ehrbar M (2013) A versatile approach to engineering biomolecule-presenting cellular microenvironments. Adv Healthc Mater 2(2):292–296PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Lima ALL, Oliveira PR, Carvalho VC, Cimerman S, Savio E (2014) Recommendations for the treatment of osteomyelitis. Braz J Infect Dis 18(5):526–534PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Lin C-C, Fu S-J, Lin Y-C, Yang I-K, Gu Y (2014) Chitosan-coated electrospun PLA fibers for rapid mineralization of calcium phosphate. Int J Biol Macromol 68:39–47PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Locs J, Li W, Sokolova M, Roether JA, Loca D, Boccaccini AR (2015) Zoledronic acid impregnated and poly (L-lactic acid) coated 45S5 Bioglass®-based scaffolds. Mater Lett 156:180–182CrossRefGoogle Scholar
  70. 70.
    Long M, Rack H (1998) Titanium alloys in total joint replacement—a materials science perspective. Biomaterials 19(18):1621–1639PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Longhi A, Errani C, De Paolis M, Mercuri M, Bacci G (2006) Primary bone osteosarcoma in the pediatric age: state of the art. Cancer Treat Rev 32(6):423–436PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Luetke A, Meyers PA, Lewis I, Juergens H (2014) Osteosarcoma treatment–where do we stand? A state of the art review. Cancer Treat Rev 40(4):523–532CrossRefGoogle Scholar
  73. 73.
    McLaren JS, White L, Cox H, Ashraf W, Rahman C, Blunn G, Goodship A, Quirk R, Shakesheff KM, Bayston R (2014) A biodegradable antibiotic-impregnated scaffold to prevent osteomyelitis in a contaminated in vivo bone defect model. Eur Cell Mater 27:332–349PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Meng Z, Zheng W, Li L, Zheng Y (2011) Fabrication, characterization and in vitro drug release behavior of electrospun PLGA/chitosan nanofibrous scaffold. Mater Chem Phys 125(3):606–611CrossRefGoogle Scholar
  75. 75.
    Mi H-Y, Salick MR, Jing X, Jacques BR, Crone WC, Peng X-F, Turng L-S (2013) Characterization of thermoplastic polyurethane/polylactic acid (TPU/PLA) tissue engineering scaffolds fabricated by microcellular injection molding. Mater Sci Eng C 33(8):4767–4776CrossRefGoogle Scholar
  76. 76.
    Mitra D, Whitehead J, Yasui OW, Leach JK (2017) Bioreactor culture duration of engineered constructs influences bone formation by mesenchymal stem cells. Biomaterials 146:29–39PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Mouriño V, Boccaccini AR (2009) Bone tissue engineering therapeutics: controlled drug delivery in three-dimensional scaffolds. J R Soc Interface: rsif20090379Google Scholar
  78. 78.
    Ngiam M, Liao S, Patil AJ, Cheng Z, Chan CK, Ramakrishna S (2009) The fabrication of nano-hydroxyapatite on PLGA and PLGA/collagen nanofibrous composite scaffolds and their effects in osteoblastic behavior for bone tissue engineering. Bone 45(1):4–16PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Nguyen BNB, Moriarty RA, Kamalitdinov T, Etheridge JM, Fisher JP (2017) Collagen hydrogel scaffold promotes mesenchymal stem cell and endothelial cell coculture for bone tissue engineering. J Biomed Mater Res A 105(4):1123–1131PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Niinomi M (2003) Recent research and development in titanium alloys for biomedical applications and healthcare goods. Sci Technol Adv Mater 4(5):445–454CrossRefGoogle Scholar
  81. 81.
    Oonishi H, Kushitani S, Yasukawa E, Iwaki H, Hench LL, Wilson J, Tsuji E, Sugihara T (1997) Particulate bioglass compared with hydroxyapatite as a bone graft substitute. Clin Orthop Relat Res 334:316–325CrossRefGoogle Scholar
  82. 82.
    Pehlivan SB, Yavuz B, Çalamak S, Ulubayram K, Kaffashi A, Vural I, Çakmak HB, Durgun ME, Denkbaş EB, Ünlü N (2015) Preparation and in vitro/in vivo evaluation of cyclosporin a-loaded nanodecorated ocular implants for subconjunctival application. J Pharm Sci 104(5):1709–1720PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Peter M, Binulal N, Nair S, Selvamurugan N, Tamura H, Jayakumar R (2010) Novel biodegradable chitosan–gelatin/nano-bioactive glass ceramic composite scaffolds for alveolar bone tissue engineering. Chem Eng J 158(2):353–361CrossRefGoogle Scholar
  84. 84.
    Petite H, Viateau V, Bensaid W, Meunier A, de Pollak C, Bourguignon M, Oudina K, Sedel L, Guillemin G (2000) Tissue-engineered bone regeneration. Nat Biotechnol 18(9):959–963PubMedCrossRefGoogle Scholar
  85. 85.
    Pirhonen E, Moimas L, Haapanen J (2003) Porous bioactive 3-D glass fiber scaffolds for tissue engineering applications manufactured by sintering technique. Key Eng Mater 240–242: 237–240. Trans Tech PublicationsGoogle Scholar
  86. 86.
    Place ES, George JH, Williams CK, Stevens MM (2009) Synthetic polymer scaffolds for tissue engineering. Chem Soc Rev 38(4):1139–1151PubMedCrossRefGoogle Scholar
  87. 87.
    Porter JR, Ruckh TT, Popat KC (2009) Bone tissue engineering: a review in bone biomimetics and drug delivery strategies. Biotechnol Prog 25(6):1539–1560PubMedGoogle Scholar
  88. 88.
    Prabaharan M, Jayakumar R (2009) Chitosan-graft-β-cyclodextrin scaffolds with controlled drug release capability for tissue engineering applications. Int J Biol Macromol 44(4):320–325PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Rahaman MN, Day DE, Bal BS, Fu Q, Jung SB, Bonewald LF, Tomsia AP (2011) Bioactive glass in tissue engineering. Acta Biomater 7(6):2355–2373PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Raisz LG (1999) Physiology and pathophysiology of bone remodeling. Clin Chem 45(8):1353–1358PubMedPubMedCentralGoogle Scholar
  91. 91.
    Ramchandani M, Robinson D (1998) In vitro and in vivo release of ciprofloxacin from PLGA 50: 50 implants. J Control Release 54(2):167–175PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Raymond AK, Jaffe N (2009) Osteosarcoma multidisciplinary approach to the management from the pathologist’s perspective. In: Pediatric and adolescent osteosarcoma. Springer, New York, pp 63–84CrossRefGoogle Scholar
  93. 93.
    Reichert JC, Hutmacher DW (2011) Bone tissue engineering. In: Tissue engineering. Springer, Berlin/Heidelberg, pp 431–456CrossRefGoogle Scholar
  94. 94.
    Rezwan K, Chen Q, Blaker J, Boccaccini AR (2006) Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering. Biomaterials 27(18):3413–3431PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Ritter J, Bielack S (2010) Osteosarcoma. Annals Oncol 21(suppl_7):vii320–vii325Google Scholar
  96. 96.
    Rivron NC, Raiss CC, Liu J, Nandakumar A, Sticht C, Gretz N, Truckenmüller R, Rouwkema J, van Blitterswijk CA (2012) Sonic Hedgehog-activated engineered blood vessels enhance bone tissue formation. Proc Natl Acad Sci 109(12):4413–4418PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Robling AG, Castillo AB, Turner CH (2006) Biomechanical and molecular regulation of bone remodeling. Annu Rev Biomed Eng 8:455–498PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Saiz E, Zimmermann EA, Lee JS, Wegst UG, Tomsia AP (2013) Perspectives on the role of nanotechnology in bone tissue engineering. Dent Mater 29(1):103–115PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Sarıgöl E, Bozdağ Pehlivan S, Ekizoğlu M, Sağıroğlu M, Çalış S (2017) Design and evaluation of gamma-sterilized vancomycin hydrochloride-loaded poly (ɛ-caprolactone) microspheres for the treatment of biofilm-based medical device-related osteomyelitis. Pharm Dev Technol 22(6):706–714PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Sarıgöl E, Ekizoğlu M, Pehlivan SB, Bodur E, Sağıroğlu M, Çalış S (2018) A thermosensitive gel loaded with an enzyme and an antibiotic drug for the treatment of periprosthetic joint infection. J Drug Delivery Sci Technol 43:423–429CrossRefGoogle Scholar
  101. 101.
    Schmidmaier G, Lucke M, Wildemann B, Haas NP, Raschke M (2006) Prophylaxis and treatment of implant-related infections by antibiotic-coated implants: a review. Injury 37(2):S105–S112PubMedCrossRefGoogle Scholar
  102. 102.
    Sears NA, Seshadri DR, Dhavalikar PS, Cosgriff-Hernandez E (2016) A review of three-dimensional printing in tissue engineering. Tissue Eng Part B Rev 22(4):298–310PubMedCrossRefGoogle Scholar
  103. 103.
    Shao H, Sun M, Zhang F, Liu A, He Y, Fu J, Yang X, Wang H, Gou Z (2018) Custom repair of mandibular bone defects with 3D printed bioceramic scaffolds. J Dent Res 97(1):68–76PubMedCrossRefGoogle Scholar
  104. 104.
    Sidney LE, Heathman TR, Britchford ER, Abed A, Rahman CV, Buttery LD (2014) Investigation of localized delivery of diclofenac sodium from poly (D, L-lactic acid-co-glycolic acid)/poly (ethylene glycol) scaffolds using an in vitro osteoblast inflammation model. Tissue Eng A 21(1–2):362–373Google Scholar
  105. 105.
    Somayaji B, Jariwala U, Jayachandran P, Vidyalakshmi K, Dudhani RV (1998) Evaluation of antimicrobial efficacy and release pattern of tetracycline and metronidazole using a local delivery system. J Periodontol 69(4):409–413PubMedCrossRefGoogle Scholar
  106. 106.
    Song Y-Y, Schmidt-Stein F, Bauer S, Schmuki P (2009) Amphiphilic TiO2 nanotube arrays: an actively controllable drug delivery system. J Am Chem Soc 131(12):4230–4232PubMedCrossRefGoogle Scholar
  107. 107.
    Soundrapandian C, Sa B, Datta S (2009) Organic–inorganic composites for bone drug delivery. AAPS PharmSciTech 10(4):1158–1171PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Stevens MM (2008) Biomaterials for bone tissue engineering. Mater Today 11(5):18–25CrossRefGoogle Scholar
  109. 109.
    Sun M, Chen M, Wang M, Hansen J, Baatrup A, Dagnaes-Hansen F, Rölfing J, Jensen J, Lysdahl H, Li H (2016) In vivo drug release behavior and osseointegration of a doxorubicin-loaded tissue-engineered scaffold. RSC Adv 6(80):76237–76245CrossRefGoogle Scholar
  110. 110.
    Suresh S, Saifuddin A (2007) Radiological appearances of appendicular osteosarcoma: a comprehensive pictorial review. Clin Radiol 62(4):314–323PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Ta HT, Dass CR, Choong PF, Dunstan DE (2009) Osteosarcoma treatment: state of the art. Cancer Metastasis Rev 28(1–2):247–263PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Taepaiboon P, Rungsardthong U, Supaphol P (2006) Drug-loaded electrospun mats of poly (vinyl alcohol) fibres and their release characteristics of four model drugs. Nanotechnology 17(9):2317–2329CrossRefGoogle Scholar
  113. 113.
    Tande AJ, Patel R (2014) Prosthetic joint infection. Clin Microbiol Rev 27(2):302–345PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Tarafder S, Bose S (2014) Polycaprolactone-coated 3D printed tricalcium phosphate scaffolds for bone tissue engineering: in vitro alendronate release behavior and local delivery effect on in vivo osteogenesis. ACS Appl Mater Interfaces 6(13):9955–9965PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Tarafder S, Balla VK, Davies NM, Bandyopadhyay A, Bose S (2013) Microwave-sintered 3D printed tricalcium phosphate scaffolds for bone tissue engineering. J Tissue Eng Regen Med 7(8):631–641PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Vivanco J, Slane J, Nay R, Simpson A, Ploeg H-L (2011) The effect of sintering temperature on the microstructure and mechanical properties of a bioceramic bone scaffold. J Mech Behav Biomed Mater 4(8):2150–2160PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Vivanco J, Aiyangar A, Araneda A, Ploeg H-L (2012) Mechanical characterization of injection-molded macro porous bioceramic bone scaffolds. J Mech Behav Biomed Mater 9:137–152PubMedCrossRefGoogle Scholar
  118. 118.
    Wang DA, Williams CG, Yang F, Elisseeff JH (2004) Enhancing the tissue-biomaterial Interface: tissue-initiated integration of biomaterials. Adv Funct Mater 14(12):1152–1159CrossRefGoogle Scholar
  119. 119.
    Wang X, Hunter D, Xu J, Ding C (2015) Metabolic triggered inflammation in osteoarthritis. Osteoarthr Cartil 23(1):22–30PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Wang X, Xu S, Zhou S, Xu W, Leary M, Choong P, Qian M, Brandt M, Xie YM (2016) Topological design and additive manufacturing of porous metals for bone scaffolds and orthopaedic implants: a review. Biomaterials 83:127–141PubMedCrossRefGoogle Scholar
  121. 121.
    Wiesmann H, Meyer U, Plate U, Hohling H (2005) Aspects of collagen mineralization in hard tissue formation. Int Rev Cytol 242:121–156PubMedCrossRefGoogle Scholar
  122. 122.
    Williams JM, Adewunmi A, Schek RM, Flanagan CL, Krebsbach PH, Feinberg SE, Hollister SJ, Das S (2005) Bone tissue engineering using polycaprolactone scaffolds fabricated via selective laser sintering. Biomaterials 26(23):4817–4827PubMedCrossRefGoogle Scholar
  123. 123.
    Woesz A, Rumpler M, Stampfl J, Varga F, Fratzl-Zelman N, Roschger P, Klaushofer K, Fratzl P (2005) Towards bone replacement materials from calcium phosphates via rapid prototyping and ceramic gelcasting. Mater Sci Eng C 25(2):181–186CrossRefGoogle Scholar
  124. 124.
    Wolinsky JB, Colson YL, Grinstaff MW (2012) Local drug delivery strategies for cancer treatment: gels, nanoparticles, polymeric films, rods, and wafers. J Control Release 159(1):14–26PubMedCrossRefGoogle Scholar
  125. 125.
    Wolstenholme GEW, O’Connor M (2009) Bone structure and metabolism. Wiley, ChichesterGoogle Scholar
  126. 126.
    Xynos ID, Edgar AJ, Buttery LD, Hench LL, Polak JM (2000) Ionic products of bioactive glass dissolution increase proliferation of human osteoblasts and induce insulin-like growth factor II mRNA expression and protein synthesis. Biochem Biophys Res Commun 276(2):461–465PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Yang S, Leong K-F, Du Z, Chua C-K (2002) The design of scaffolds for use in tissue engineering. Part II. Rapid prototyping techniques. Tissue Eng 8(1):1–11PubMedCrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of Pharmaceutical Technology, Faculty of PharmacyAnkara UniversityAnkaraTurkey

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