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Bidirectional differentiation of BMSCs induced by a biomimetic procallus based on a gelatin-reduced graphene oxide reinforced hydrogel for rapid bone regeneration

ABSTRACT: Developmental engineering strategy needs the biomimetic composites that can integrate the progenitor cells, biomaterial matrices and bioactive signals to mimic the natural bone healing process for faster healing and reconstruction of segmental bone defects. We prepared the gelatin-reduced graphene oxide (GOG) and constructed the composites that mimicked the procallus by combining the GOG with the photo-crosslinked gelatin hydrogel. The biological effects of the GOG-reinforced composites could induce the bi-differentiation of bone marrow stromal cells (BMSCs) for rapid bone repair. The proper ratio of GOG in the composites regulated the composites' mechanical properties to a suitable range for the adhesion and proliferation of BMSCs. Besides, the GOG-mediated bidirectional differentiation of BMSCs, including osteogenesis and angiogenesis, could be activated through Erk1/2 and AKT pathway. The methyl vanillate (MV) delivered by GOG also contributed to the bioactive signals of the biomimetic procallus through priming the osteogenesis of BMSCs. During the repair of the calvarial defect in vivo, the initial hypoxic condition due to GOG in the composites gradually transformed into a well-vasculature robust situation with the bi-differentiation of BMSCs, which mimicked the process of bone healing resulting in the rapid bone regeneration. As an inorganic constituent, GOG reinforced the organic photo-crosslinked gelatin hydrogel to form a double-phase biomimetic procallus, which provided the porous extracellular matrix microenvironment and bioactive signals for the bi-directional differentiation of BMSCs. These show a promised application of the bio-reduced graphene oxide in biomedicine with a developmental engineering strategy. Graphical abstract Image 1 Highlights • The gelatin-reduced graphene oxide (GOG) was used to reinforce the photo-crosslinked gelatin hydrogel.• The GOG reinforced composite hydrogel was constructed to mimic the procallus for bone regeneration.• The bi-differentiation of bone marrow stromal cells (BMSCs) could be induced by the composite hydrogel.

SUBMITTER: Jiao D

PROVIDER: S-EPMC7782557 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Project description:In clinical trials, new scaffolds for regeneration after spinal cord injury (SCI) should reflect the importance of a mechanically optimised, hydrated environment. Composite scaffolds of nonwovens, self-assembling peptides (SAPs) and hydrogels offer the ability to mimic native spinal cord tissue, promote aligned tissue regeneration and tailor mechanical properties. This work studies the effects of an aligned electrospun nonwoven of P11-8-enriched poly(ε-caprolactone) (PCL) fibres, integrated with a photo-crosslinked hydrogel of glycidylmethacrylated collagen (collagen-GMA), on neurite extension. Mechanical properties of collagen-GMA hydrogel in compression and shear were recorded, along with cell viability. Collagen-GMA hydrogels showed J-shaped stress-strain curves in compression, mimicking native spinal cord tissue. For hydrogels prepared with a 0.8-1.1 wt.% collagen-GMA concentration, strain at break values were 68 ± 1-81 ± 1% (±SE); maximum stress values were 128 ± 9-311 ± 18 kPa (±SE); and maximum force values were 1.0 ± 0.1-2.5 ± 0.1 N (±SE). These values closely mimicked the compression values for feline and porcine tissue in the literature, especially those for 0.8 wt.%. Complex shear modulus values fell in the range 345-2588 Pa, with the lower modulus hydrogels in the range optimal for neural cell survival and growth. Collagen-GMA hydrogel provided an environment for homogenous and three-dimensional cell encapsulation, and high cell viability of 84 ± 2%. Combination of the aligned PCL/P11-8 electrospun nonwoven and collagen-GMA hydrogel retained fibre alignment and pore structure, respectively, and promoted aligned neurite extension of PC12 cells. Thus, it is possible to conclude that scaffolds with mechanical properties that both closely mimic native spinal cord tissue and are optimal for neural cells can be produced, which also promote aligned tissue regeneration when the benefits of hydrogels and electrospun nonwovens are combined.

Project description:Biocompatible reduced graphene oxide (rGO) could deliver drugs for synergistically stimulating stem cells directed differentiation with influences on specific cellular activities. Here, we prepared a biodegradable gelatin reduced graphene oxide (rGO@Ge) to evaluate its functions in promoting rat adipose derived mesenchymal stem cells (ADSCs) chondrogenic differentiation through delivering kartogenin (KGN) into the stem cell efficiently. The optimum KGN concentration (approximately 1 μM) that promoted the proliferation and chondrogenic differentiation of ADSCs was clarified by a series of experiments, including immunofluorescent (IF) staining (Sox-9, Col II), alcian blue (Ab) staining, toluidine blue (Tb) staining and real-time quantitative PCR analysis of the chondrogenic markers. Meanwhile, the biocompatibility of rGO@Ge was evaluated to clearly define the nonhazardous concentration range, and the drug loading and releasing properties of rGO@Ge were tested with KGN for its further application in inducing ADSCs chondrogenic differentiation. Furthermore, the mechanism of rGO@Ge entering ADSCs was investigated by the different inhibitors that are involved in the endocytosis of the nanocarrier, and the degradation of the rGO@Ge in ADSCs was observed by transmission electron microscopy (TEM). The synergistic promoting effect of rGO@Ge nanocarrier on ADSCs chondrogenesis with KGN was also studied by the IF, Ab, Tb stainings and PCR analysis of the chondrogenic markers. Finally, the intracellular Reactive Oxygen Species (ROS) and autophagy induced by KGN/rGO@Ge complex composites were tested in details for clarification on the correlation between the autophagy and chondrogenesis in ADSCs induced by rGO@Ge. All the results show that rGO@Ge as a biocompatible nanocarrier can deliver KGN into ADSCs for exerting a pro-chondrogenic effect and assist the drug to promote ADSCs chondrogenesis synergistically through modification of the autophagy in vitro, which promised its further application in repairing cartilage defect in vivo.

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Bidirectional differentiation of BMSCs induced by a biomimetic procallus based on a gelatin-reduced graphene oxide reinforced hydrogel for rapid bone regeneration

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