Inorganic Nanoparticles in Bone Healing Applications

Abstract

Modern biomedicine aims to develop integrated solutions that use medical, biotechnological, materials science, and engineering concepts to create functional alternatives for the specific, selective, and accurate management of medical conditions. In the particular case of tissue engineering, designing a model that simulates all tissue qualities and fulfills all tissue requirements is a continuous challenge in the field of bone regeneration. The therapeutic protocols used for bone healing applications are limited by the hierarchical nature and extensive vascularization of osseous tissue, especially in large bone lesions. In this regard, nanotechnology paves the way for a new era in bone treatment, repair and regeneration, by enabling the fabrication of complex nanostructures that are similar to those found in the natural bone and which exhibit multifunctional bioactivity. This review aims to lay out the tremendous outcomes of using inorganic nanoparticles in bone healing applications, including bone repair and regeneration, and modern therapeutic strategies for bone-related pathologies.

Keywords: bioceramic nanoparticles; bone regeneration; inorganic nanoparticles; metallic nanoparticles; oxide nanoparticles.

Figure 1

Schematic representation of hydroxyapatite nanoparticles (HANPs) in bone healing applications.

Figure 2

Quantitative representation of bone regeneration induced in rat femur defects by bare nano-hydroxyapatite/poly(lactide-co-glycolide) scaffolds (nHA-PLGA), nHA/PLGA scaffolds modified with BMP-2, VEGF, and FGF-2 (BVF/nHA-PLGA), and nHA/PLGA scaffolds modified with BMP-2-loaded poly(lactic-co-glycolic acid)-poly(ethylene glycol)-carboxyl microparticles and VEGF/FGF-2-loaded gelatin microparticles (B-PPC_mp/VF-GEL_mp/nHA-PLGA), evidenced at 12 weeks post-implantation by bone volume fractions (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.n), trabecular spacing (Tb.Sp), and bone mineral density (BMD). Each data point represents the mean ± standard deviation (n = 3), and statistically significant differences are indicated as ∗ p < 0.05, ∗∗ p < 0.01, ∗∗∗ p < 0.001, and ∗∗∗∗ p < 0.0001. See Ref. [117]. Reprinted from an open access source.

Figure 3

Quantitative representation of mortality (death rate, %) in zebrafish embryos treated with mesoporous fluoride-doped nano-hydroxyapatite (0.6, 1.2, and 3.2 at.% for FHAp-1, FHAp-2, and FHAp-3, respectively) with respect to time and concentration. The as-developed FHAp nanorods also exhibited important concentration-dependent antibacterial effects against Pseudomonas aeruginosa and Bacillus subtilis. See Ref. [192]. Reprinted from an open access source.

Figure 4

Schematic representation of bioactive glass/polymer composites in bone healing applications.

Figure 5

Micro-computed tomography (μ-CT) images of the infected rat tibia (control group), evidencing signs of infection at 8 weeks: narrowing of marrow space, presence of puss-filled fibrous capsule, sinus tract, and deformed bone with ectopic bone growth (red arrows) (a). μ-CT images of the infected rat tibia treated with vancomycin-loaded polymer/BG bone void-filling putty at 8 weeks post-implantation, evidencing signs of healing bone, as well as the formation of cortical and cancellous bone in the drilling space (green arrows) (b). The as-developed scaffolds also determined the in vivo eradication of Staphylococcus aureus. See Ref. [262]. Reprinted from an open access source.

Figure 6

Histological analysis and immunostaining in the femur of osteoporotic mice at 3 weeks post-treatment with mesoporous silica nanoparticles (MSNs) grafted with alendronate-modified poly(ethylene glycol) and poly(ethylene imine) (MSNs-PA@PEI), parathyroid hormone (PTH), and MSNs-PA@PEI loaded with osteostatin and sclerostin-encoding plasmid (OST-SiRNA), evidencing: representative micrographs of different femur histological sections after hematoxylin/eosin and Masson–Goldner trichrome staining (A); representative Runx2 immunostaining in mice femurs, revealed by the abundant positivity (brown stains) for the transcription factor in cells after PTH or OST-siRNA treatments (B); total and sclerostin-positive osteocytes in the cortical femur (C). Data are represented as mean ± standard error of mean of five independent mice (n = 5), and the statistical significance is indicated as # p < 0.001 vs. control, * p < 0.05 vs. ovariectomized mice (OVX), and ** p < 0.001 vs. OVX. See Ref. [302]. Reprinted from an open access source.

Figure 7

Schematic representation of stimuli-responsive mesoporous silica nanoparticles (MSNs).

Figure 8

Three-dimensional μ-CT reconstruction images of trabecular bone in ovariectomized mice (OVX), OVX treated with hydroxyapatite-coated superparamagnetic iron oxide nanocomposites (SPIO@15HA) and sham group (A), and trabecular bone mass parameters (B), evidenced after 3 months post-injection. BMD—bone mineral density, BV/TV—bone volume fractions, Tb.N—trabecular number, Tb.Th—trabecular thickness, Tb.Sp—trabecular spacing, Conn.D—connectivity density. Data are expressed as mean ± standard deviation of seven independent mice (n = 7), ns means no significance, and the statistical significance is indicated as * p  <  0.05, ** p  <  0.01, and *** p  <  0.001. See Ref. [370]. Reprinted from an open access source.

Figure 9

Histological analysis of rat cranial defects treated with bare and nano-ceria-loaded polycaprolactone/gelatin membranes (PG M and PG-CeO₂ M, respectively) for 4 and 8 weeks (w), evidenced by Masson’s trichrome staining. Control group (a,d), PG M group (b,e), and PG-CeO₂ M group (c,f). M—membrane, B—bone, scale bar—100 μm. See Ref. [417]. Reprinted from an open access source.

Figure 10

Histological analysis of rabbit skull defects treated with bare and nano-silver-loaded gelatin/alginate scaffolds (Gel/Alg and AgNP–Gel/Alg, respectively) for 4 weeks (A) and 8 weeks (B), evidenced by Masson staining (100×). Gel/Alg group (a,e); 200 μM AgNP–Gel/Alg group (b,f); 400 μM AgNP–Gel/Alg group (c,g); 600 μM AgNP–Gel/Alg group (d,h). See Ref. [475]. Reprinted from an open access source.