Engineering pre-vascularized bone-like tissue from human mesenchymal stem cells through simulating endochondral ossification.

Currently, most in vitro engineered bone tissues do not contain viable blood vessel systems, so the vascularization depends on post-implantation angiogenesis from the host, which is often insufficient for repairing large bone defects. In this study, we aimed to create pre-vascularized bone-like tissue from human bone marrow-derived mesenchymal stem cells (HBMSCs) within the self-generated extracellular matrix by simulating the developmental endochondral ossification. Afterward, a three-dimensional (3D) culture of human umbilical vein endothelial cells (HUVECs)/HBMSCs was introduced to cover bone-like constructs surface for vascularization. Lastly, the pre-vascularized bone-like tissues were subcutaneously implanted into mice and the quality of newly formed blood vessels and bones were later assessed. We particularly examined whether the pre-existing HUVECs/HBMSCs vascular networks within the implants were able to integrate with the host's blood vessels and facilitate bone formation. Our results showed that this developmentally informed procedure resulted in a robust osteogenic differentiation of HBMSCs. Moreover, the bone-like constructs markedly promoted HUVEC/HBMSCs network formation in vitro. After 28 days of implantation in mice, the experimental group, in which bone-like constructs were pre-vascularized with HUVEC/HBMSCs networks, exhibited significantly more functional blood vessels than the control group that contained HUVEC and HBMSC single cells. Interestingly, increased levels of bone formation and absorption markers were also observed in the pre-vascularized bone-like constructs. Taken together, these findings demonstrated the potential of pre-vascularized bone-like constructs in repairing bone defects.

Graphene oxide-functionalized nanocomposites promote osteogenesis of human mesenchymal stem cells via enhancement of BMP-SMAD1/5 signaling pathway.

Biomaterials that can harness the intrinsic osteogenic potential of stem cells offer a promising strategy to accelerate bone regeneration and repair. Previously, we had used methacrylated gelatin (GelMA)-based scaffolds to achieve bone formation from human mesenchymal stem cells (hMSCs). In this study, we aimed to further enhance hMSC osteogenesis by incorporating graphene oxide (GO)-based nanosheets into GelMA. In vitro results showed high viability and metabolic activities in hMSCs encapsulated in the newly developed nanocomposites. Incorporation of GO markedly increased mineralization within hMSC-laden constructs, which was further increased by replacing GO with silica-coated graphene oxide (SiGO). Mechanistic analysis revealed that the nanosheet enhanced the production, retention, and biological activity of endogenous bone morphogenetic proteins (BMPs), resulting in robust osteogenesis in the absence of exogenous osteoinductive growth factors. Specifically, the osteoinductive effect of the nanosheets was abolished by inhibiting the BMP signaling pathway with LDN-193189 treatment. The bone formation potential of the technology was further tested in vivo using a mouse subcutaneous implantation model, where hMSCs-laden GO/GelMA and SiGO/GelMA samples resulted in bone volumes 108 and 385 times larger, respectively, than the GelMA control group. Taken together, these results demonstrate the biological activity and mechanism of action of GO-based nanosheets in augmenting the osteogenic capability of hMSCs, and highlights the potential of leveraging nanomaterials such as GO and SiGO for bone tissue engineering applications.

Lack of Agreement on Distal Radius Fracture Treatment.

INTRODUCTION: Variation in clinical practice resulting from the absence of evidence-based treatment protocols has negative implications on both the cost and the quality of medical care. The objective of this study was to assess whether a standard of care for the treatment of extra-articular nondisplaced distal radius fracture has developed despite the lack of a conclusive recommendation from the American Academy of Orthopaedic Surgeons. METHODS: A case-vignette survey was conducted. Treatment type and duration of casting selections were analyzed. The cost implications of responses were assessed. Participants were practicing orthopedists primarily in the mid-Atlantic region of the United States. Orthopedists (n = 494) were recruited via E-mail and at the American Academy of Orthopaedic Surgeons Annual Meeting held in Chicago in March 2013. Inclusion criteria required that participants be graduates of an accredited medical school and be practicing orthopedists at the time of survey distribution. The main outcome measure was surgical or nonsurgical intervention. RESULTS: Nonsurgical treatment was selected by 60% of respondents, with surgery preferred by 37%. Duration of casting responses varied from 2 to 12 weeks. Among nonsurgical responses, 69% indicated 6 weeks as their preferred duration of casting (95% confidence interval, 64.9-73.1%). Surgery imposes a 76% greater total cost to society than nonsurgical treatments. CONCLUSIONS: Our findings suggest the absence of a consensus strategy for the treatment of extra-articular nondisplaced distal radius fractures. Implications of variance in treatment on cost and quality support the need for established, evidence-based guidelines or further clinical trials to assist in the management of this common fracture.