Magnetic hydroxyapatite: a promising multifunctional platform for nanomedicine application

Abstract

In this review, specific attention is paid to the development of nanostructured magnetic hydroxyapatite (MHAp) and its potential application in controlled drug/gene delivery, tissue engineering, magnetic hyperthermia treatment, and the development of contrast agents for magnetic resonance imaging. Both magnetite and hydroxyapatite materials have excellent prospects in nanomedicine with multifunctional therapeutic approaches. To date, many research articles have focused on biomedical applications of nanomaterials because of which it is very difficult to focus on any particular type of nanomaterial. This study is possibly the first effort to emphasize on the comprehensive assessment of MHAp nanostructures for biomedical applications supported with very recent experimental studies. From basic concepts to the real-life applications, the relevant characteristics of magnetic biomaterials are patented which are briefly discussed. The potential therapeutic and diagnostic ability of MHAp-nanostructured materials make them an ideal platform for future nanomedicine. We hope that this advanced review will provide a better understanding of MHAp and its important features to utilize it as a promising material for multifunctional biomedical applications.

Keywords: drug delivery; hydroxyapatite; hyperthermia; iron oxide; tissue engineering.

Figure 1

Different synthesis routes of MHAp nanostructures. Schematic illustration of (A) formation mechanism of one-dimensional MHAp nanorods, (B) synthesis of ultrathin MHAp nanosheet (HAPUN/MNs), and (C) chemical precipitation and hydrothermal synthesis of MHAp. (A) Reproduced from Bharath G, Prabhu D, Mangalaraj D, Viswanathan C, Ponpandian N. Facile in situ growth of Fe₃O₄ nanoparticles on hydroxyapatite nanorods for pH dependent adsorption and controlled release of proteins. RSC Adv. 2014;4(92):50510–50520 with permission of The Royal Society of Chemistry. (B) Reproduced from Chen F, Li C, Zhu YJ, Zhao XY, Lu BQ, Wu J. Magnetic nanocomposite of hydroxyapatite ultrathin nanosheets/Fe₃O₄ nanoparticles: microwave-assisted rapid synthesis and application in pH-responsive drug release. Biomater Sci. 2013;1(10):1074–1081 with permission of The Royal Society of Chemistry. Abbreviations: MHAp, magnetic hydroxyapatite; HAp, hydroxyapatite; CTAB, N-cetyl-N,N,N-trimethyl ammonium bromide.

Figure 2

MHAp structure synthesized in different shapes (A–H). (A) Reproduced from Cui X, Green MA, Blower PJ, et al. Al(OH)₃ facilitated synthesis of water-soluble, magnetic, radiolabelled and fluorescent hydroxyapatite nanoparticles. Chem Commun (Camb). 2015;51(45):9332–9335 with permission of The Royal Society of Chemistry. (B) Reproduced from Lin K, Chen L, Liu P, et al. Hollow magnetic hydroxyapatite microspheres with hierarchically mesoporous microstructure for pH-responsive drug delivery. CrystEngComm. 2013;15(15):2999–3008 with permission of The Royal Society of Chemistry. (C) Reprinted with permission from Boda SK, Anupama AV, Basu B, Sahoo B. Structural and magnetic phase transformations of hydroxyapatite magnetite composites under inert and ambient sintering atmospheres. J Phys Chem C. 2015;119(2):6539–6555. Copyright 2015 American Chemical Society. (D) Reproduced from Chen F, Li C, Zhu YJ, Zhao XY, Lu BQ, Wu J. Magnetic nanocomposite of hydroxyapatite ultrathin nanosheets/Fe₃O₄ nanoparticles: microwave-assisted rapid synthesis and application in pH-responsive drug release. Biomater Sci. 2013;1(10):1074–1081 with permission of The Royal Society of Chemistry. (E) Reproduced from Lin K, Chen L, Liu P, et al. Hollow magnetic hydroxyapatite microspheres with hierarchically mesoporous microstructure for pH-responsive drug delivery. CrystEngComm. 2013;15(15):2999–3008 with permission of The Royal Society of Chemistry. (F) Reprinted from Singh RK, El-Fiqi AM, Patel KD, Kim HW. A novel preparation of magnetic hydroxyapatite nanotubes. Mater Lett. 2012;75:130–133. Copyright 2012, with permission from Elsevier. (G) Reproduced from Bharath G, Prabhu D, Mangalaraj D, Viswanathan C, Ponpandian N. Facile in situ growth of Fe₃O₄ nanoparticles on hydroxyapatite nanorods for pH dependent adsorption and controlled release of proteins. RSC Adv. 2014;4(92):50510–50520 with permission of The Royal Society of Chemistry. (H) Reproduced from Cui X, Green MA, Blower PJ, et al. Al(OH)₃ facilitated synthesis of water-soluble, magnetic, radiolabelled and fluorescent hydroxyapatite nanoparticles. Chem Commun (Camb). 2015;51(45):9332–9335 with permission of The Royal Society of Chemistry. (I) Reproduced from Bharath G, Prabhu D, Mangalaraj D, Viswanathan C, Ponpandian N. Facile in situ growth of Fe₃O₄ nanoparticles on hydroxyapatite nanorods for pH dependent adsorption and controlled release of proteins. RSC Adv. 2014;4(92):50510–50520 with permission of The Royal Society of Chemistry. Abbreviation: MHAp, magnetic hydroxyapatite.

Figure 3

(A) SEM images of new bone tissue growing inside and around magnetic scaffolds: (a) MAG-A; (b) a detail of MAG-A; and (c) MAG-B at 4 weeks. Scaffold delimited by yellow dashed line; red arrows show mineralization. (b′ and d) Osteocyte lacunae (indicated by asterisks) in the new bone grown inside MAG-A and MAG-B, respectively. Scale bars: (a and c) 1.0 mm; (b) 300 μm; and (d) 100 μm. Reprinted from Panseri S, Russo A, Sartori M, et al. Modifying bone scaffold architecture in vivo with permanent magnets to facilitate fixation of magnetic scaffolds. Bone. 2013;56(2):432–439. Copyright 2013, with permission from Elsevier. (B) Merged images in (a) show magnetic field lines coming out from permanent magnet and resulting scaffold orientation. (b) Schematic presentation of magnet–scaffold fixation with four implanted permanent magnet pins (PM) that hold an osteochondral scaffold. Reprinted from Panseri S, Russo A, Sartori M, et al. Modifying bone scaffold architecture in vivo with permanent magnets to facilitate fixation of magnetic scaffolds. Bone. 2013;56(2):432–439. Copyright 2013, with permission from Elsevier. Abbreviations: MAG-A, magnetic scaffold A; SEM, scanning electron microscopy.

Figure 4

Schematic presentation of scaffolds magnetization process: (1) scaffold is immersed in 1 mL of ferrofluid for 15 min; (2) scaffold is freeze-dried for 24 h; (3) scaffold is rinsed with deionized water under ultrasonication for 20 min; (4) scaffold is freeze-dried for 24 h; and (5) magnetized scaffold is obtained.

Figure 5

Representative histological views of (A, C, E, and G) HAp and (B, D, F, and H) MHAp scaffolds stained with toluidine blue, acid fuchsin, and fast green at (A–D) 4 and (E–H) 12 weeks from implantation. The low magnification reported in images (A, B, E, and F) allows the displaying of the entire scaffold (dark) and of the implant site. Scale bar is 1 mm in (A, B, E, and F) and 500 mm in (C, D, G, and H). Reproduced from Russo A, Bianchi M, Sartori M, et al. Bone regeneration in a rabbit critical femoral defect by means of magnetic hydroxyapatite macroporous scaffolds. J Biomed Mater Res B Appl Biomater. Epub 2017 Feb 15. Copyright 2017 Wiley. Abbreviations: HAp, hydroxyapatite; MHAp, magnetic hydroxyapatite.

Figure 6

Schematic diagram of MHAp scaffold-enhanced MC3T3-E1 cell proliferation, showing that MAPK/ERK signaling pathway was activated by the protein corona formed on the surface of MHAp scaffold to promote cell proliferation. Reprinted with permission from Zhu Y, Yang Q, Yang M, et al. Protein corona of magnetic hydroxyapatite scaffold improves cell proliferation via activation of mitogen-activated protein kinase signaling pathway. ACS Nano. 2017;11(4):3690–3704. Copyright 2017 American Chemical Society. Abbreviations: MHAp, magnetic hydroxyapatite; HAp, hydroxyapatite.

Figure 7

Drug and protein release kinetics of different MHAp nanostructures at different pH conditions. (A) The cumulative drug release percentages of docetaxel from the HAPUN/MNs nanocomposite drug delivery system in PBS with different pH values of 7.4 and 4.5. Reproduced from Chen F, Li C, Zhu YJ, Zhao XY, Lu BQ, Wu J. Magnetic nanocomposite of hydroxyapatite ultrathin nanosheets/Fe₃O₄ nanoparticles: microwave-assisted rapid synthesis and application in pH-responsive drug release. Biomater Sci. 2013;1(10):1074–1081 with permission of The Royal Society of Chemistry. (B) Cell viability tests of the HAPUN/MNs without and with docetaxel drug loading. Reproduced from Chen F, Li C, Zhu YJ, Zhao XY, Lu BQ, Wu J. Magnetic nanocomposite of hydroxyapatite ultrathin nanosheets/Fe₃O₄ nanoparticles: microwave-assisted rapid synthesis and application in pH-responsive drug release. Biomater Sci. 2013;1(10):1074–1081 with permission of The Royal Society of Chemistry. Cumulative release of hemoglobin loaded on (C) Fe₃O₄/HAp-1 and (D) Fe₃O₄/HAp-2 nanocomposites at different initial pH values of 7.4 and 9.0 in PBS at room temperature. Reproduced from Bharath G, Prabhu D, Mangalaraj D, Viswanathan C, Ponpandian N. Facile in situ growth of Fe₃O₄ nanoparticles on hydroxyapatite nanorods for pH dependent adsorption and controlled release of proteins. RSC Adv. 2014;4(92):50510–50520 with permission of The Royal Society of Chemistry. Abbreviations: MHAp, magnetic hydroxyapatite; PBS, phosphate buffer solution; HAp, hydroxyapatite; Hb, hemoglobin; Dtxl, docetaxel; HAPUN/MN, HAp ultrathin nanosheet.

Figure 8

In vivo PL imaging of the mice after subcutaneous injection (A) without and (B) with Eu³⁺/Gd³⁺-HAp (Eu³⁺:Gd³⁺ =1:2) nanorods. (C) PL emission images of Eu³⁺/Gd³⁺-HAp nanorods at different concentrations. The excitation wavelength was 430 nm. Reprinted from Chen F, Huang P, Zhu YJ, Wu J, Zhang CL, Cui DX. The photolu minescence, drug delivery and imaging properties of multifunctional Eu³⁺/Gd³⁺ dual-doped hydroxyapatite nanorods. Biomaterials. 2011;32(34):9031–9039. Copyright 2011 with permission from Elsevier. Abbreviations: PL, photoluminescence; HAp, hydroxyapatite.

Figure 9

T2-weighted MR images of liver: (A) stage I, normal liver, (B) stage II, acute hepatic injury which is 4 h after CCl₄ gavage, and (C) stage III, with the contrast enhancement of the HAp-ION-90 nanoworm. Histochemical analysis of (D) normal hepatic area and (E) injured hepatic area. All scale bars: 20 μm. Reproduced from Xu YJ, Dong L, Lu Y, et al. Magnetic hydroxyapatite nanoworms for magnetic resonance diagnosis of acute hepatic injury. Nanoscale. 2016;8(3):1684–1690 with permission of The Royal Society of Chemistry. Abbreviations: MR, magnetic resonance; HAp, hydroxyapatite; i, Stage I; ii, Stage II; iii, Stage III.

Figure 10

The clinical photographs of the mouse treated with MHAp on magnetic field exposure. The tumor on (A) day 1, (B) day 5, and (C) day 14 is shown. Reprinted from Hou CH, Hou SM, Hsueh YS, Lin J, Wu HC, Lin FH. The in vivo performance of biomagnetic hydroxyapatite nanoparticles in cancer hyperthermia therapy. Biomaterials. 2009;30(23–24):3956–3960. Copyright 2009, with permission from Elsevier. Abbreviation: MHAp, magnetic hydroxyapatite.

Figure 11

(A) Schematic representation of magnetofection for gene delivery. (B) Schematic illustration of DNA loading into lamellar MHAp nanoparticles for nucleic acid delivery. Abbreviation: MHAp, magnetic hydroxyapatite.