Modified composite microspheres of hydroxyapatite and poly(lactide-co-glycolide) as an injectable scaffold
Graphical abstract
Introduction
The tissue engineering scaffold prepared by biomimetic materials is a promising scaffold [1], [2], [3]. Biomimetic scaffold materials are expected to elicit specific cellular responses between materials and cells, which will lead to the formation of new tissue. Since the chemical and structural characteristics of hydroxyapatite (HA) are similar to the mineral phase of native bone, HA is an effective component for preparing bone tissue engineering scaffolds [4]. HA has good biocompatibility and osteoconductivity, but some drawbacks of it, such as difficulty of shaping, poor mechanical strength, brittleness and slow degradation rate, limit its application in bone tissue [5], [6], [7]. It is hoped that composites of HA and other biomaterials can overcome the defects mentioned above [8], [9], [10], [11].
Much attention has also been paid to composites of HA and synthetic polylactone-type biodegradable polymers, such as poly(l-lactide), polyglycolide and their copolymer poly(lactide-co-glycolide) (PLGA). Since the polymers possess good mechanical properties, low immunogenicity and toxicity, and an adjustable degradation rate, they have been widely used as scaffold materials of tissue engineering. The combination of HA and polylactone-type polymers can be expected to obtain the optimum scaffold materials for bone tissue engineering.
The composite materials of polylactone-type polymer and HA have been widely researched in bone tissue engineering [12], [13], [14], [15]. Usually, the composite materials were prepared by a simply physical mixing method, but in the ordinary blending system, only physical adsorption is achieved between HA particles and polymer matrix. Consequently, the interface adhesion of HA particles and polymer matrix is weak, which led to occur easily phase detach of the polymer and HA. So, to increase the interfacial strength between the two phases, various methods have been tried in the past [16], [17], [18], [19].
Various shape scaffolds such as film, rod, plate, block, foam and microsphere have been fabricated using the composite materials of polylactone-type polymer and HA [12], [20], [21], [22], [23], [24], [25], [26]. Among them microsphere-type scaffold can provide more versatile applications than pre-shaped scaffolds. For example, it can perform tissue repair and gene therapy when loaded with special growth factors or drugs. On the other hand, microsphere-type scaffolds also possess other advantages, such as needing only a minor incision and a more convenient operation for the scaffold transplantation. So, it is necessary to prepare an injectable microsphere-type scaffold. The microspheres can be mixed with cells and then injected as a three-dimensional scaffold into various shaped bone defects for bone repair.
The composite microspheres of HA and polylactone-type polymer have generally been fabricated by an emulsion–solvent evaporation method [27], [28]. However, there was little HA exposed on the surface of composite microspheres prepared by the emulsion-solvent evaporation method using simply mixture of HA and polymer. To make HA exposed to surface of microspheres, in our previous work, the composite microsphere were treated by a mixture of 0.25 M NaOH aqueous solution and ethanol (v/v = 1/1) at 37 °C [29]. Although a good result was obtained, the microspheres were damaged in certain degree. Furthermore, other researchers prepared HA-coated polylactone-type polymer microspheres by a Pickering emulsion route using interaction between carbonyl/carboxylic acid groups of PLLA and HA nanoparticles at the dichloromethane–water interface [30], [31], [32]. But the effect of these microspheres on osteoblast growth still was undefined. In addition, HA-coated PLGA microspheres also were fabricated by incubating PLGA microspheres in simulated body fluid [33]. But the HA-coated PLGA easily gathered together, which would influence the injectability of microspheres.
The aim of this study was to develop a reactive microsphere of HA and polylactone-type polymer as an injectable bone tissue engineering scaffold that owned good interfacial strength and rich HA on the surface. First, HA modified PLGA (HA-PLGA) was prepared by reaction of PLGA and HA. Then the HA-PLGA composite microspheres were fabricated by an emulsion–solvent evaporation method. The morphology and properties of the HA-PLGA composite microspheres were investigated by scanning electron microscopy (SEM), energy-dispersive spectroscopy (EDS) and X-ray photoelectron spectra (XPS). Finally, adhesion, proliferation and differentiation of cells on the HA-PLGA composite microspheres were evaluated and compared with that on the composite microspheres prepared by the simple mixture of HA and PLGA (HA/PLGA) using the mouse OCT-1 osteoblast-like cell as a model cell in vitro.
Section snippets
Materials
Glycolide and lactide were purchased from Acros Chemica, N.V. and purified twice by recrystallization in ethyl acetate. Stannous octoate (Sigma, A.R.) was used without further purification. Ethyl acetate was dried by P2O5 overnight and then distilled. Hydroxyapatite was purchased from Sinopharm Chemical Reagent Co., Ltd., China and used after being grinded to 2.62 μm of average particle size. Poly(vinyl alcohol) (PVA, average Mn = 77,000, 87–89% hydrolyzed) was purchased from Tianjin Zongheng
Synthesis and characterization of HA-PLGA
To enhance the interaction between HA and polymer matrix, HA has been modified with carboxyl and phosphate compounds such as hexanoic acid [35], decanoic acid [35], hydroxystearic acid [36], oleic acid [37], stearic acid [38], sodium dodecyl sulfate [39] and alkyl phosphates [40] by hydrogen bond, electrostatic interaction, hydrophilic/hydrophobic interaction, ionic bond and chemical bond. Especially, Hong et al. prepared a surface modification of HA via ring-opening graft polymerization of l
Conclusion
HA-PLGA prepared by ionic bond between PLGA and HA was more stable than the HA/PLGA composite prepared by simple physical mixture of PLGA and HA. HA-PLGA effectively overcame the easy phase separation defect of HA/PLGA composite. HA was more easily exposed to the surface of the HA-PLGA microspheres, which improved the less HA defect of HA/PLGA microsphere surface. Compare with HA/PLGA microspheres, HA-PLGA microspheres were more suitable for cell attachment, growth and differentiation. HA-PLGA
Acknowledgements
This research was financially supported by a grant from National Natural Science Foundation for Young scholars of china (No. 51103165 and 31200717).
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