Effect of Dual Releasing of β-glycerophosphate and Dexamethasone from Ti Nanostructured Surface for Using in Orthopedic Applications

Document Type : Original Article


1 Department of Biomedical Engineering, Science and Research Branch, Islamic Azad University, Tehran, Iran

2 b Department of Nanotechnology and Advanced Materials, Materials and Energy Research Center (MERC), Karaj, Iran


Nano-structured surface and its ability to dual release of osteogenic and anti-inflammatory agents have a positive effect on the success of using titanium in orthopedic applications. For this purpose, TiO2 nanotubes (TNTs) were created via anodization method on Ti sheets and loaded by β-glycerophosphate (GP) and dexamethasone (DEX) as osteogenic and anti-inflammatory agents, respectively. They were coated with a polyvinyl alcohol (PVA) layer for controlling their releasing rate. The synthesized dual-release system was characterized by field emission scanning electron microscopy (FE-SEM), Fourier transform infrared spectroscopy (FTIR) analysis, XRD and UV-Vis techniques. The average diameter of TNTs was 84.182 nm. The presence of drugs in the system has been proven in the FTIR analysis. UV-Vis technique’s results show that the coated layer could control the release rate to improve the potential of the structures for supporting mineralization. Releasing of DEX was higher than GP and reached to a constant rate after 9 days. MTT test results confirmed the possibility of the surface designed Ti for bone regeneration purposes.


1. Jalali, N., Moztarzadeh, F., Mozafari, M., Asgari, S., Shokri, S.
and Alhosseini, S.N., "Chitosan-surface modified poly (lactideco-glycolide)
2011 18th Iranian Conference of Biomedical Engineering 
(ICBME), IEEE., (2011), 109-114. 
2. Demirdöğen, R.E., Emen, F.M., Ocakoglu, K., Murugan, P.,
Sudesh, K. and Avşar, G., "Green nanotechnology for synthesis
and characterization of poly (3-hydroxybutyrate-co-3hydroxyhexanoate)
nanoparticles for sustained bortezomib
release using supercritical CO
 assisted particle formation
combined with electrodeposition", International Journal of
Biological Macromolecules,  Vol. 107, (2018), 436-445. 
3. Liang, P.-C., Huang, K.-W., Tung, C.-C., Chang, M.-C., Chang,
F.-Y., Wong, J.-M. and Chang, Y.-T., "A novel photodynamic
therapy-based drug delivery system layered on a stent for treating
cholangiocarcinoma", Biomedical Microdevices,  Vol. 20, No. 1,
(2018), DOI: 10.1007/s10544-017-0249-1. 
4. Tan, Y., Zhu, Y., Zhao, Y., Wen, L., Meng, T., Liu, X., Yang, X.,
Dai, S., Yuan, H. and Hu, F., "Mitochondrial alkaline phresponsive
drug release mediated by celastrol loaded glycolipid-
like micelles for cancer therapy", Biomaterials,  Vol. 154, (2018),
5. Nicolas, J., Mura, S., Brambilla, D., Mackiewicz, N. and
Couvreur, P., "Design, functionalization strategies and
biomedical applications of targeted biodegradable/biocompatible
polymer-based nanocarriers for drug delivery", Chemical Society
Reviews,  Vol. 42, No. 3, (2013), 1147-1235. 
6. Sadrnezhaad, S. and Abbaspour, S., "Loading drug on
nanostructured ti6al4v-ha for implant applications",
International Journal of Engineering-Transaction B:
Applications, Vol. 31, No. 8, (2018), 1159-1165. 
7. Liu, N., Chen, X., Zhang, J. and Schwank, J.W., "A review on
tio2-based nanotubes synthesized via hydrothermal method:
Formation mechanism, structure modification, and photocatalytic
applications", Catalysis Today,  Vol. 225, (2014), 34-51. 
8. Nourmohammadi, A., Mehrjueeb, M. and Bahrevarc, M.,
"Electrophoretic synthesis of titanium oxide nanotubes",
International Journal of Engineering-Transactions A: Basics, 
Vol. 25, No. 4, (2012), 343-350. 
9. Wang, J., Li, H., Sun, Y., Bai, B., Zhang, Y. and Fan, Y.,
"Anodization of highly ordered TiO
 nanotube arrays using
orthogonal design and its wettability", International Journal of
Electrochemical Science,  Vol. 11, (2016), 710-723. 
10. Wilczewska, A.Z., Niemirowicz, K., Markiewicz, K.H. and Car,
H., "Nanoparticles as drug delivery systems", Pharmacological
Reports,  Vol. 64, No. 5, (2012), 1020-1037. 
11. Wei, F., Li, M., Crawford, R., Zhou, Y. and Xiao, Y., "Exosomeintegrated
titanium oxide nanotubes for targeted bone
regeneration", Acta Biomaterialia,  Vol. 86, (2019), 480-492. 
12. Paulose, M., Peng, L., Popat, K.C., Varghese, O.K., LaTempa,
T.J., Bao, N., Desai, T.A. and Grimes, C.A., "Fabrication of
mechanically robust, large area, polycrystalline
nanotubular/porous TiO
 membranes", Journal of Membrane
Science,  Vol. 319, No. 1-2, (2008), 199-205. 
13. Prakasam, H.E., Shankar, K., Paulose, M., Varghese, O.K. and
Grimes, C.A., "A new benchmark for TiO
 nanotube array growth
by anodization", The Journal of Physical Chemistry C,  Vol.
111, No. 20, (2007), 7235-7241. 
14. Wen, J., Li, Q., Li, H., Chen, M., Hu, S. and Cheng, H., "Nano-
 imparts amidoximated wool fibers with good antibacterial
activity and adsorption capacity for uranium (vi) recovery",
Industrial & Engineering Chemistry Research,  Vol. 57, No. 6,
(2018), 1826-1833. 
15. Zhang, T., Xie, C., Liu, Y., Zhang, F. and Xiao, X., "Phresponsive
drug release system of Cu
-modified ammoniated
 nanotube arrays", Materials Letters,  Vol. 215, (2018), 9598.
16. Oh, S.-H., Finones, R.R., Daraio, C., Chen, L.-H. and Jin, S.,
"Growth of nano-scale hydroxyapatite using chemically treated
titanium oxide nanotubes", Biomaterials,  Vol. 26, No. 24,
(2005), 4938-4943. 
17. Zhang, W., Zhang, Z. and Zhang, Y., "The application of carbon
nanotubes in target drug delivery systems for cancer therapies",
Nanoscale Research Letters,  Vol. 6, No. 1, (2011), 555. 
18. von der Mark, K., Bauer, S., Park, J. and Schmuki, P., "Another
look at “stem cell fate dictated solely by altered nanotube
dimension”", Proceedings of the National Academy of Sciences, 
Vol. 106, No. 24, (2009), E60-E60. 
19. Johari, N., Hosseini, H.R.M. and Samadikuchaksaraei, A., "Novel
fluoridated silk fibroin/ TiO
 nanocomposite scaffolds for bone
tissue engineering", Materials Science and Engineering: C,  Vol.
82, (2018), 265-276. 
20. Shidfar, S., Tavangarian, F., Nemati, N.H. and Fahami, A., "Drug
delivery behavior of titania nanotube arrays coated with chitosan
polymer", Materials Discovery,  Vol. 8, (2017), 9-17. 
21. Christensen, D.B. and Farris, K.B., "Pharmaceutical care in
community pharmacies: Practice and research in the us", Annals
of Pharmacotherapy,  Vol. 40, No. 7-8, (2006), 1400-1406. 
22. Torkildsen, G., Abelson, M.B., Gomes, P.J., McLaurin, E., Potts,
S.L. and Mah, F.S., "Vehicle-controlled, phase 2 clinical trial of
a sustained-release dexamethasone intracanalicular insert in a
chronic allergen challenge model", Journal of Ocular
Pharmacology and Therapeutics,  Vol. 33, No. 2, (2017), 79-90. 
23. Chaudhary, N., Arora, I., Gupta, D. and Gupta, C.P., "Comparison
of efficacy and safety of dexamethasone 0.1% and difluprednate
0.05% in the management of ocular inflammation after
phacoemulsification", Journal of Evolution of Medical and
Dental Sciences-Jemds,  Vol. 4, No. 74, (2015), 12899-12903. 
24. Wang, Q., Jiang, H., Li, Y., Chen, W., Li, H., Peng, K., Zhang, Z.
and Sun, X., "Targeting nf-kb signaling with polymeric hybrid
micelles that co-deliver sirna and dexamethasone for arthritis
therapy", Biomaterials,  Vol. 122, (2017), 10-22. 
25. Euba, B., Moleres, J., Segura, V., Viadas, C., Morey, P., Moranta,
D., Leiva, J., de-Torres, J.P., Bengoechea, J.A. and Garmendia,
J., "Genome expression profiling-based identification and
administration efficacy of host-directed antimicrobial drugs
against respiratory infection by nontypeable haemophilus
influenzae", Antimicrobial Agents and Chemotherapy,  Vol. 59,
No. 12, (2015), 7581-7592. 
26. Khodaverdi, E., Kheirandish, F., Mirzazadeh Tekie, F.S.,
Khashyarmanesh, B.Z., Hadizadeh, F. and Moallemzadeh
Haghighi, H., "Preparation of a sustained release drug delivery
system for dexamethasone by a thermosensitive, in situ forming
hydrogel for use in differentiation of dental pulp", ISRN
Pharmaceutics,  Vol. 2013, (2013), DOI: 10.1155/2013/983053. 
27. Park, J.-B., "The effects of dexamethasone, ascorbic acid, and βglycerophosphate
on osteoblastic differentiation by regulating
estrogen receptor and osteopontin expression", Journal of
Surgical Research,  Vol. 173, No. 1, (2012), 99-104. 
28. Hamlin, N. and Price, P., "Mineralization of decalcified bone
occurs under cell culture conditions and requires bovine serum
but not cells", Calcified Tissue International,  Vol. 75, No. 3,
(2004), 231-242. 
29. Boskey, A.L., Guidon, P., Doty, S.B., Stiner, D., Leboy, P. and
Binderman, I., "The mechanism of β‐glycerophosphate action in
mineralizing chick limb‐bud mesenchymal cell cultures",
Journal of Bone and Mineral Research,  Vol. 11, No. 11, (1996),
30. Kamoun, E.A., Kenawy, E.-R.S. and Chen, X., "A review on
polymeric hydrogel membranes for wound dressing applications:
Pva-based hydrogel dressings", Journal of Advanced Research, 
Vol. 8, No. 3, (2017), 217-233. 
31. Kayal, S. and Ramanujan, R., "Doxorubicin loaded pva coated
iron oxide nanoparticles for targeted drug delivery", Materials
Science and Engineering: C,  Vol. 30, No. 3, (2010), 484-490. 
32. Ohtsuki, C., "How to prepare the simulated body fluid (SBF) and
its related solutions, proposed by kokubo and his colleagues",
Graduate school of materials science, Nara Institute of Science
and Technology,  (2009). 
33. Chen, L., Tang, C., Chen, D., Wong, C. and Tsui, C., "Fabrication
and characterization of poly-dl-lactide/nano-hydroxyapatite
composite scaffolds with poly (ethylene glycol) coating and
dexamethasone releasing", Composites Science and Technology, 
Vol. 71, No. 16, (2011), 1842-1849. 
34. Kumar, P.M., Badrinarayanan, S. and Sastry, M.,
"Nanocrystalline TiO
 studied by optical, ftir and x-ray
photoelectron spectroscopy: Correlation to presence of surface
states", Thin Solid Films,  Vol. 358, No. 1-2, (2000), 122-130. 
35. Sahoo, P., Panda, H. and Bahadur, D., "Studies on the stability
and kinetics of drug release of dexamethasone phosphate 
intercalated layered double hydroxides nanohybrids", Materials
Chemistry and Physics,  Vol. 142, No. 1, (2013), 106-112. 
36. Mabrouk, M., Mostafa, A., Oudadesse, H., Mahmoud, A.A. and
El-Gohary, M.I., "Effect of ciprofloxacin incorporation in pva and
pva bioactive glass composite scaffolds", Ceramics
International,  Vol. 40, No. 3, (2014), 4833-4845. 
37. Aw, M.S., Gulati, K. and Losic, D., "Controlling drug release
from titania nanotube arrays using polymer nanocarriers and
biopolymer coating", Journal of Biomaterials and
Nanobiotechnology,  Vol. 2, No. 05, (2011), 477-484. 
38. Fratzl-Zelman, N., Fratzl, P., Hörandner, H., Grabner, B., Varga,
F., Ellinger, A. and Klaushofer, K., "Matrix mineralization in 
mc3t3-e1 cell cultures initiated by β-glycerophosphate pulse",
Bone,  Vol. 23, No. 6, (1998), 511-520. 
39. Vacanti, N.M., Cheng, H., Hill, P.S., Guerreiro, J.o.D., Dang,
T.T., Ma, M., Watson, S.e., Hwang, N.S., Langer, R. and
Anderson, D.G., "Localized delivery of dexamethasone from
electrospun fibers reduces the foreign body response",
Biomacromolecules,  Vol. 13, No. 10, (2012), 3031-3038. 
40. Szymaǹska, E., Sosnowska, K., Miltyk, W., Rusak, M., Basa, A.
and Winnicka, K., "The effect of β-glycerophosphate crosslinking
on chitosan cytotoxicity and properties of hydrogels for vaginal
application", Polymers,  Vol. 7, No. 11, (2015), 2223-2244.