Sodium alendronate loaded poly(L-lactideco-glycolide)microparticles immobilized on ceramic scaffolds for local treatment of bone defects

Bone tissue regeneration in critical-size defects is possible after implantation of a 3D scaffold and can be additionally enhanced once the scaffold is enriched with drugs or other factors supporting bone remodelling and healing.Sodium alendronate(Aln),a widely used anti-osteoporosis drug,exhibits strong inhibitory effect on bone resorption performed by osteoclasts.Thus,we propose a new approach for the treatment of bone defects in craniofacial region combining biocompatible titanium dioxide scaffolds and poly(L-lactide-co-glycolide)microparticles(MPs)loaded with Aln.The MPs were effectively attached to the surface of the scaffolds’pore walls by human recombinant collagen.Drug release from the scaffolds was characterized by initial burst(2466% of the drug released within first 24 h)followed by a sustained release phase(on average 5 mg of Aln released per day from Day 3 to Day 18).In vitro tests evidenced that Aln at concentrations of 5 and 2.5 mg/ml was not cytotoxic for MG-63 osteoblast-like cells(viability between 8166% and 9863% of control),but it prevented RANKL-induced formation of osteoclast-like cells from macrophages derived from peripheral blood mononuclear cells,as shown by reduced fusion capability and decreased tartrateresistant acid phosphatase 5b activity(5665% reduction in comparison to control after 8 days of culture).Results show that it is feasible to design the scaffolds providing required doses of Aln inhibiting osteoclastogenesis,reducing osteoclast activity,but not affecting osteoblast functions,which may be beneficial in the treatment of critical-size bone tissue defects.

Biomimetic hydroxyapatite coating on the 3D-printed bioactive porous composite ceramic scaffolds promoted osteogenic differentiation via PI3K/AKT/mTOR signaling pathways and facilitated bone regeneration in vivo

The architecture and surface modifications have been regarded as effective methods to enhance the bi-ological response of biomaterials in bone tissue engineering.The porous architecture of the implanta-tion was essential conditions for bone regeneration.Meanwhile,the design of biomimetic hydroxyap-atite(HAp)coating on porous scaffolds was demonstrated to strengthen the bioactivity and stimulate osteogenesis.However,bioactive bio-ceramics such asβ-tricalcium phosphate(β-TCP)and calcium sili-cate(CS)with superior apatite-forming ability were reported to present better osteogenic activity than that of HAp.Hence in this study,3D-printed interconnected porous bioactive ceramicsβ-TCP/CS scaf-fold was fabricated and the biomimetic HAp apatite coating were constructed in situ via hydrothermal reaction,and the effects of HAp apatite layer on the fate of mouse bone mesenchymal stem cells(mBM-SCs)and the potential mechanisms were explored.The results indicated that HAp apatite coating en-hanced cell proliferation,alkaline phosphatase(ALP)activity,and osteogenic gene expression.Further-more,PI3K/AKT/mTOR signaling pathway is proved to have an important impact on cellular functions.The present results demonstrated that the key molecules of phosphatidylinositol 3-kinase(PI3K),protein kinase B(AKT)and mammalian target of rapamycin(mTOR)were activated after the biomimetic hydrox-yapatite coating were constructed on the 3D-printed ceramic scaffolds.Besides,the activated influence on the protein expression of Runx2 and BMP2 could be suppressed after the treatment of inhibitor HY-10358.In vivo studies showed that the constructed HAp coating promoted bone formation and strengthen the bone quality.These results suggest that biomimetic HAp coating constructed on the 3D-printed bioac-tive composite scaffolds could strengthen the bioactivity and the obtained biomimetic multi-structured scaffolds might be a potential alternative bone graft for bone regeneration.

Ultra-lightweight ceramic scaffolds with simultaneous improvement of pore interconnectivity and mechanical strength

The high porosity and interconnectivity of scaffolds are critical for nutrient transmission in bone tis-sue engineering but usually lead to poor mechanical properties.Herein,a novel method that combines acid etching(AE)with selective laser sintering(SLS)and reaction bonding(RB)of Al particles is pro-posed to realize highly improved porosity,interconnectivity,mechanical strength,and in vitro bioactivity in 3D Al_(2)O_(3) scaffolds.By controlling the oxidation and etching behaviors of Al particles,a tunable hol-low spherical feature can be obtained,which brings about the distinction in compressive response and fracture path.The prevention of microcrack propagation on the in situ formed hollow spheres results in unique near elastic buckling rather than traditional brittle fracture,allowing an unparalleled compressive strength of 3.72±0.17 MPa at a high porosity of 87.7%±0.4%and pore interconnectivity of 94.7%±0.4%.Furthermore,scaffolds with an optimized pore structure and superhydrophilic surface show excellent cell proliferation and adhesion properties.Our findings offer a promising strategy for the coexistence of out-standing mechanical and biological properties,with great potential for tissue engineering applications.

Sodium alendronate loaded poly(L-lactideco-glycolide)microparticles immobilized on ceramic scaffolds for local treatment of bone defects

Bone tissue regeneration in critical-size defects is possible after implantation of a 3D scaffold and can be additionally enhanced once the scaffold is enriched with drugs or other factors supporting bone remodelling and healing.Sodium alendronate(Aln),a widely used anti-osteoporosis drug,exhibits strong inhibitory effect on bone resorption performed by osteoclasts.Thus,we propose a new approach for the treatment of bone defects in craniofacial region combining biocompatible titanium dioxide scaffolds and poly(L-lactide-co-glycolide)microparticles(MPs)loaded with Aln.The MPs were effectively attached to the surface of the scaffolds’pore walls by human recombinant collagen.Drug release from the scaffolds was characterized by initial burst(2466%of the drug released within first 24 h)followed by a sustained release phase(on average 5 mg of Aln released per day from Day 3 to Day 18).In vitro tests evidenced that Aln at concentrations of 5 and 2.5 mg/ml was not cytotoxic for MG-63 osteoblast-like cells(viability between 8166%and 9863%of control),but it prevented RANKL-induced formation of osteoclast-like cells from macrophages derived from peripheral blood mononuclear cells,as shown by reduced fusion capability and decreased tartrateresistant acid phosphatase 5b activity(5665%reduction in comparison to control after 8 days of culture).Results show that it is feasible to design the scaffolds providing required doses of Aln inhibiting osteoclastogenesis,reducing osteoclast activity,but not affecting osteoblast functions,which may be beneficial in the treatment of critical-size bone tissue defects.

Enhancement of the Pore Interconnectivity and Porosity of Calcium Phosphate Scaffolds by Acid-Etching Method

Porous hydroxyapatite （HA）-tricalcium phosphate （TCP） ceramic scaffolds were prepared using a screw-type extrusion method with polymer beads. HA and dicalcium phosphate dehydrates （DCPD） were added at various ratios to obtain different HA/TCP ratios in sintered ceramic scaffolds. To further enhance the pore interconnectivity and porosity, the developed porous ceramic scaffolds were etched with acid solutions. The maximum porosity （- 85%） was observed in the Ca-P scaffold with the lowest HA （-7%） content. On the other hand, the maximum compressive strength was noted in the scaffolds with the highest HA content （ - 85%）. X-ray diffraction showed that the extent of the fl-TCP to a-TCP phase transformation increased with decreasing HA/DCPD ratio. All HCl-etched scaffolds were observed to generate micropores, which improved the interconnectivity, while biomineralization was found to be the same for both the HCl-etched and non- etched scaffolds. In particular, hydrochloric acid etching is a promising method for improving the interconnectivity and porosity of the ceramic scaffolds.