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The regenerative repair of large bone defects is a major problem in orthopedics and clinical medicine. The key problem is the lack of ability of existing bone graft materials to promote osteogenesis and angiogenesis. Previous studies have shown that the osteogenic or angiogenic abilities of these materials could be significantly improved by adding miRNA or small-molecule drugs to bone graft materials; however, the synergistic effect arising from this combination is not clear. Therefore, we proposed to construct a dual drug delivery system that could simultaneously achieve the co-encapsulation and co-delivery of miRNA and small-molecule drugs to explore the effect of a dual drug delivery system on bone repair. In this study, we constructed dual-sized pore structure calcium-silicon nanospheres (DPNPs) and achieved the co-encapsulation of miR-210, angiogenic gene drugs, and simvastatin (Siv), a small-molecule osteogenic drug, through metal-ion coordination and physical adsorption. In vitro and in vivo osteogenic and angiogenic experiments showed that the dual drug delivery system (Siv/DPNP/miR-210) exhibited better properties than those of the individual unloaded and single drug-loaded systems and could significantly accelerate the process of bone repair, which provides a novel strategy for the regeneration and repair of bone defects.

Melatonin (MT) has been served as promising osteogenic factor to promote osteogenesis. However, the direct injection of MT is accompanied by its fast diffusion and rapid degradation, which can significantly affect the repairing of bone defects. The sustainable release of MT from scaffolds would greatly enhance bone regeneration, but it has never been studied. Herein, we have demonstrated the decoration of MT molecules into the 3D-printed beta-tricalcium phosphate (β-TCP) scaffolds by utilizing the dopamine-based mussel-inspired chemistry. The slower release of MT from the scaffolds was achieved, and bone mesenchymal stem cells demonstrated great viability and proliferation ability within the scaffolds. Remarkably, a significantly higher expression of osteogenic-genes was achieved in the MT decorated scaffolds in the presence of dopamine. These scaffolds were then implanted into rat calvarial defect sites for the in vivo bone regeneration investigation. Micro-computed tomography (micro-CT), bone mineral density and histological analysis clearly revealed that the scaffolds with MT decoration exhibited the highest percentage of new bone ingrowth. These results demonstrate that the decoration of MT into the 3D-printed β-TCP scaffolds could be a facile and highly efficient strategy to promote bone regeneration.

Cellular behavior is a result of homologous responses to biomaterials, especially material surfaces. An effective way to elicit a desired biological response is to employ micro/nanostructured constructions for biomaterial surface design; however, the brittleness of inorganic materials usually hinders structure regulation. In this study, a micro/nanostructured surface was fabricated using a hydrothermal treatment that did not require crystal regulation reagents. The precursor, β-tricalcium phosphate, was mixed with CaSiO3. The resulting micro/nanostructured surface had a hybrid structure containing nanowires, microrods, and rod clusters. In vitro cellular proliferation, cytotoxicity and osteodifferentiation experiments indicated that the micro/nanostructured surfaces alleviated material cytotoxicity, improved cell proliferation, and effectively promoted osteogenic differentiation of mouse bone mesenchymal stem cells. These results suggest that this simplified surface treatment is an efficient way to improve cell biological response to inorganic biomaterials.

Material properties and cellular behaviours seemed to be coupled, implying the existence of reciprocities between cells and materials. Understanding cellular behaviours and material structure is indispensable for materials synthesis and design but has mostly focused on shape, neglecting the status of the sub-structure. Hence we utilized a similar route to regulate the different morphology of HAp particles and then investigated reciprocities between particles and bone marrow mesenchymal stem cells (BMSCs). Based on our cell experiment, we revealed the side effects of dissociated micro-rods on cellular behaviours. Despite the facts that both particles showed modestly cytotoxicity, the multi-structure HAp sphere could positively-regulate the proliferation, viability and differentiation of bone marrow mesenchymal stem cells (BMSCs) which indicated that the dissociated micro-rods may deteriorate the biological properties in vitro.

A well-designed scaffold with accurately controlled structure, pore size as well as interconnection plays a key role in tissue engineering. In this study, porous Li-containing biphasic calcium phosphate scaffolds (Li-BCP) with expected structure were fabricated successfully by 3D plotting technique. The results of scanning electron microscopy (SEM) and micro-CT indicated that scaffolds from 3D plotting possessed an elaborate pore structure, porosity and interconnection. Besides, Li-BCP scaffolds also possessed excellent mechanical strength. Furthermore, in vitro cell experiments confirmed that mouse bone mesenchymal stem cells (mBMSCs) cultured on Li-BCP scaffolds exhibited good adhesion and spreading. Moreover, Li-BCP scaffolds could efficaciously promote the proliferation and osteogenic differentiation of mBMSCs, demonstrating their potential applicability as a candidate for bone repair applications.

Calcium phosphate ceramics have been widely used in clinics as bone grafts. However, according to traditional techniques, it is difficult to create calcium phosphate bone grafts with tailored internal porous structures that may ensure optimal biocompatibility and sufficient mechanical properties. In this study, β-TCP bone scaffolds with well-defined inter-connective porous structures were fabricated by robocasting. With the aim of better mimicking the native extracellular matrix of bone without sacrificing the mechanical strength, type I collagen gel was coated on the filaments of the sintered β-TCP scaffolds to form an ultrafine fibrous network that was similar to the natural collagen nanofibers in bone. Both sintered β-TCP scaffolds and collagen gel coated scaffolds supported the growth of mouse mesenchymal stromal cells (mMSCs). Meanwhile, the thin layer of biomimetic collagen nanofibers on the β-TCP scaffolds significantly stimulated the osteoblastic differentiation of mMSCs by up-regulating the expression of ALP, Runx-2, collagen I, OPN, BSP and BMP-2. Additionally, a more active biogenesis of matrix vesicles (MVs) was induced in the mMSCs on the collagen gel coated scaffolds, evidenced by SEM and TEM results together with a significant increase of the gene expression of matrix vesicle components, indicating an enhanced initiation of matrix mineralization. Our study not only illustrates the potential use of the collagen gel coated β-TCP robocast scaffold for bone repair but also highlights the significance of the incorporation of collagen nanofibers in the scaffolds.