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Human bone exhibits exceptional mechanical properties due to its hierarchical architecture, which span from the nano/microscopic to the macroscopic scale. The increasing incidence of orthopaedic disorders, as fractures, osteoporosis-related bone loss, and joint degeneration is a growing concern, especially among the aging population. This trend has increased the demand for effective bone graft substitute that promote regeneration, mechanical stability, and biological integration. Bone scaffolds need to provide a porous matrix with interconnected porosity to enhance tissue growth as well as sufficient strength to support physiological loads. Additionally, they must be compatible with the physiological remodelling processes mediated by osteoclasts and osteoblasts. [1] In response to these clinical and biological challenges, researchers are focusing on scaffold-based techniques. A key objective is the development of scaffolds with precise shape, mechanical strength, porosity, and biofunctionality, that replicate the hierarchical and functional complexity of natural bone. Among the techniques used for bone tissue engineering, microfluidic-assisted 3D printing offers unique advantages by enabling the fabrication of customized structures with controlled architecture. [2]
In this study, we present a microfluidic-assisted 3D printing method to fabricate functionally graded ceramic scaffold for bone regeneration. The system employs a custom flow-focusing microfluidic printhead to generate size-controlled oil-in-water emulsion. By adjusting the relative flow rates of the continuous and dispersed phases, the emulsion droplet size, and consequently the local porosity, can be modulated on-demand during printing, enabling the fabrication of scaffolds with spatially controlled gradients. A composite ink based on gelatine methacrylate (GelMA) and hydroxyapatite (HA) was selected for its biocompatibility, osteoinductivity and suitable rheological properties. Notably, the bioactivity of HA allows direct interaction with bone tissue, stimulating growth and accelerating bone healing. [3] Due to its low-viscosity, the ink was extruded into an agarose fluid gel serving as supporting bath. Through strategic emulsion generation and fiber deposition, this method enables precise control over scaffold morphology and architecture, leading to the fabrication of functionally graded porous materials (FGPMs). Morphological characterization via scanning electron microscopy (SEM) revealed that the ceramic grains fused during sintering, while micro-computed tomography (µ-CT) analysis demonstrated well-defined hierarchical internal porosity architecture of the scaffolds. Mechanical testing confirmed the stiffness of the resulting ceramic scaffold. The sintered scaffold was then seeded with human mesenchymal stem cells (hMSCs) to demonstrate how adhesion and spreading were influenced by scaffold architecture, in particular pore size, interconnectivity, and surface topography, and to assess osteogenic differentiation. These results confirmed the platform's ability to create supportive microenvironments.
In conclusion, microfluidics-based systems combined with rapid prototyping, allow the replication of bioinspired scaffolds that closely mimic the structural and mechanical features of native bone. Mechanical and morphological investigations validated the novel platform's ability to deposit high-resolution 3D structure with density gradients. This platform has great potential to progress the field of bone tissue engineering through the development of biomimetic, high-performance constructs.
[1] Wang, C. et al., Bioact Mater 5, 82–91 (2020).
[2] Marcotulli, M. et al., Adv Mater Technol 8, 2201244 (2023).
[3] Amini, AR., et al. S. P., Crit Rev Biomed Eng 40, 363–408 (2012).
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