Synthesis of Cu/Gd co-doped hydroxyapatite composite absorbable material and its application in orbital bone defect repair

Objective  To synthesize hydroxyapatite/poly (lactic-co-glycolic acid)(HA/PLGA) composites by substituting calcium ions in HA with Cu and Gd ions, characterize their physicochemical properties, and evaluate their feasibility for orbital bone defect repair.

Methods  Different ratios of Cu-, Gd-, and Cu/Gd-substituted HA nanoparticles (Cu@HA, Gd@HA and Cu/Gd@HA) were synthesized via hydrothermal synthesis using copper nitrate, gadolinium nitrate, calcium chloride, and ammonium hydrogen phosphate.HA/PLGA, Cu@HA/PLGA, Gd@HA/PLGA, and Cu/Gd@HA/PLGA composites were prepared.HA/PLGA was prepared by co-preparing different ratios of nanoparticles with PLGA via phase inversion and solvent evaporation.The nanoparticles and composites were characterized using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), inductively coupled plasma (ICP), environmental scanning electron microscope (ESEM) and micro-computed tomography (Micro-CT). Composite homogeneity was assessed by elemental analysis and the contact angle was measured to evaluate hydrophilicity.Imaging capability of composites was assessed by magnetic resonance imaging (MRI) and T1-weighted.CCK-8 method was used to detect the cytotoxicity of nanoparticles and their extract.Orbital bone defects model was established in 20 rats, which were randomly divided into 4 groups, and implanted with respective composites.Eight weeks after transplantation, the implants were evaluated using Micro-CT and MRI, and osteogenesis, collagen distribution and biocompatibility were assessed by hematoxylin-eosin staining, Masson, and Sirius red staining.All animal experiments complied with the regulations of the Laboratory Animal Ethics Committee of Dalian Medical University and were approved (No.AEE23104).

Results  XRD and ESEM results showed that co-doping with Cu/Gd induced less HA lattice distortion than single doping.FT-IR results showed that the nanoparticles doped with Cu and Gd ions were consistent with the HA infrared absorption spectrum.ICP results revealed a higher Ca content in 0.5Cu/Gd@HA and 0.5Cu@HA samples than in 0.5Gd@HA sample.There was a statistically significant overall difference in contact angles among different groups of composites ( F=5.040, P<0.05), among which the 0.5Cu/Gd@HA/PLGA composite exhibited the smallest contact angle and the best hydrophilicity.There was no statistically significant difference in porosity among different groups of composites ( F=0.004, P>0.05). MRI results showed that Gd-doped composites displayed enhanced development and that the signal intensity of the 0.5Gd@HA/PLGA group was the highest.Micro-CT scanning results showed that the composition of the composite material doped with Cu and Gd was better than that of the pure HA/PLGA group, indicating that the metal ions Cu and Gd could promote bone growth.CCK-8 results showed that the nanoparticles and their extracts had no obvious cytotoxic effects.Eight weeks after modelling, Micro-CT showed that the 0.5Cu/Gd@HA/PLGA material degraded well in vivo and the staining results of bone tissue sections in the bone defect area suggested that tissues around the implanted material and rat organs in different groups did not show biological toxicity.In addition, the Gd-doped composites showed good magnetic imaging characteristics when implanted in animals.

Conclusions  Cu/Gd@HA/PLGA composites exhibit favorable physicochemical properties, biosafety, osteogenic potential, and MRI contrast and have good clinical application prospects for orbital bone repair.

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