Abstract
Advanced fabrication methods for bone grafts designed to match defect sites that combine biodegradable, osteoconductive materials with potent, osteoinductive biologics would significantly impact the clinical treatment of large bone defects. In this study, we engineered synthetic bone grafts using a hybrid approach that combined three-dimensional (3D-)printed biodegradable, osteoconductive β-tricalcium phosphate (β-TCP) with osteoinductive microRNA(miR)-200c. 3D-printed β-TCP scaffolds were fabricated utilizing a suspension-enclosing projection-stereolithography (SEPS) process to produce constructs with reproducible microarchitectures that enhanced the osteoconductive properties of β-TCP. Collagen coating on 3D-printed β-TCP scaffolds slowed the release of plasmid DNA encoding miR-200c compared to noncoated constructs. 3D-printed β-TCP scaffolds coated with miR-200c-incorporated collagen increased the transfection efficiency of miR-200c of both rat and human BMSCs and additionally increased osteogenic differentiation of hBMSCs in vitro. Furthermore, miR-200c-incorporated scaffolds significantly enhanced bone regeneration in critical-sized rat calvarial defects. These results strongly indicate that bone grafts combining SEPS 3D-printed osteoconductive biomaterial-based scaffolds with osteoinductive miR-200c can be used as superior bone substitutes for the clinical treatment of large bone defects.
Highlights
The restoration of large bone defects after traumatic injuries, tumor resections, and congenital diseases represents complex orthopedic and plastic surgical problems that often necessitate bone grafting.[1−3] The outcomes of bone defect restoration are further complicated by factors, such as advanced age, severity of injury, degree of soft tissue damage, and comorbidities including osteoporosis and diabetes.[4]
The 3D-printed β-TCP scaffolds were fabricated from computer-aided design (CAD) files using suspensionenclosing projection-stereolithography (SEPS) and were designed to have porous channels running from the top-down and through the sides of each scaffold, creating a lattice network with interconnected pores (Figure 2A,B)
After human bone marrow mesenchymal stem cells (hBMSCs) were pipetted onto the top surface of the β-TCP scaffolds, we observed that the cells dispersed throughout the constructs
Summary
The restoration of large bone defects after traumatic injuries, tumor resections, and congenital diseases represents complex orthopedic and plastic surgical problems that often necessitate bone grafting.[1−3] The outcomes of bone defect restoration are further complicated by factors, such as advanced age, severity of injury, degree of soft tissue damage, and comorbidities including osteoporosis and diabetes.[4] While autografts are the current gold standard for treating bone defects, supply limitations and donor-site morbidity restrict their therapeutic application.[5] Allografts may be used alternatively and represent nearly one-third of all bone grafts in North America Their clinical use is hindered by issues with immunological rejection and the risk of disease transfer.[6] the geometric irregularities of bone defects make graft-defect matching extremely challenging.[7]. Previous bone regeneration studies have heavily relied on the use of osteogenic growth factors, including recombinant human bone morphogenetic proteins (rhBMP-2, rhBMP-7),[8−13] parathyroid hormone (PTH),[14,15] and others, to enhance bone regeneration in synthetic bone grafts.[16−18] recombinant growth factors are expensive and unstable, and the short half-life of these agents requires the administration of supraphysiological doses, which have been linked to a growing
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